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Trigo CM, Rodrigues JS, Camões SP, Solá S, Miranda JP. Mesenchymal stem cell secretome for regenerative medicine: Where do we stand? J Adv Res 2025; 70:103-124. [PMID: 38729561 DOI: 10.1016/j.jare.2024.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 02/27/2024] [Accepted: 05/03/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND Mesenchymal stem cell (MSC)-based therapies have yielded beneficial effects in a broad range of preclinical models and clinical trials for human diseases. In the context of MSC transplantation, it is widely recognized that the main mechanism for the regenerative potential of MSCs is not their differentiation, with in vivo data revealing transient and low engraftment rates. Instead, MSCs therapeutic effects are mainly attributed to its secretome, i.e., paracrine factors secreted by these cells, further offering a more attractive and innovative approach due to the effectiveness and safety of a cell-free product. AIM OF REVIEW In this review, we will discuss the potential benefits of MSC-derived secretome in regenerative medicine with particular focus on respiratory, hepatic, and neurological diseases. Both free and vesicular factors of MSC secretome will be detailed. We will also address novel potential strategies capable of improving their healing potential, namely by delivering important regenerative molecules according to specific diseases and tissue needs, as well as non-clinical and clinical studies that allow us to dissect their mechanisms of action. KEY SCIENTIFIC CONCEPTS OF REVIEW MSC-derived secretome includes both soluble and non-soluble factors, organized in extracellular vesicles (EVs). Importantly, besides depending on the cell origin, the characteristics and therapeutic potential of MSC secretome is deeply influenced by external stimuli, highlighting the possibility of optimizing their characteristics through preconditioning approaches. Nevertheless, the clarity around their mechanisms of action remains ambiguous, whereas the need for standardized procedures for the successful translation of those products to the clinics urges.
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Affiliation(s)
- Catarina M Trigo
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Joana S Rodrigues
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Sérgio P Camões
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Susana Solá
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Joana P Miranda
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
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Shah DD, Chorawala MR, Raghani NR, Patel R, Fareed M, Kashid VA, Prajapati BG. Tumor microenvironment: recent advances in understanding and its role in modulating cancer therapies. Med Oncol 2025; 42:117. [PMID: 40102282 DOI: 10.1007/s12032-025-02641-4] [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: 01/06/2025] [Accepted: 02/24/2025] [Indexed: 03/20/2025]
Abstract
Tumor microenvironment (TME) denotes the non-cancerous cells and components presented in the tumor, including molecules produced and released by them. Interactions between cancer cells, immune cells, stromal cells, and the extracellular matrix within the TME create a dynamic ecosystem that can either promote or hinder tumor growth and spread. The TME plays a pivotal role in either promoting or inhibiting tumor growth and dissemination, making it a critical factor to consider in the development of effective cancer therapies. Understanding the intricate interplay within the TME is crucial for devising effective cancer therapies. Combination therapies involving inhibitors of immune checkpoint blockade (ICB), and/or chemotherapy now offer new approaches for cancer therapy. However, it remains uncertain how to best utilize these strategies in the context of the complex tumor microenvironment. Oncogene-driven changes in tumor cell metabolism can impact the TME to limit immune responses and present barriers to cancer therapy. Cellular and acellular components in tumor microenvironment can reprogram tumor initiation, growth, invasion, metastasis, and response to therapies. Components in the TME can reprogram tumor behavior and influence responses to treatments, facilitating immune evasion, nutrient deprivation, and therapeutic resistance. Moreover, the TME can influence angiogenesis, promoting the formation of blood vessels that sustain tumor growth. Notably, the TME facilitates immune evasion, establishes a nutrient-deprived milieu, and induces therapeutic resistance, hindering treatment efficacy. A paradigm shift from a cancer-centric model to a TME-centric one has revolutionized cancer research and treatment. However, effectively targeting specific cells or pathways within the TME remains a challenge, as the complexity of the TME poses hurdles in designing precise and effective therapies. This review highlights challenges in targeting the tumor microenvironment to achieve therapeutic efficacy; explore new approaches and technologies to better decipher the tumor microenvironment; and discuss strategies to intervene in the tumor microenvironment and maximize therapeutic benefits.
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Affiliation(s)
- Disha D Shah
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, Gujarat, 380009, India
| | - Mehul R Chorawala
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, Gujarat, 380009, India.
| | - Neha R Raghani
- Department of Pharmacology and Pharmacy Practice, Saraswati Institute of Pharmaceutical Sciences, Gandhinagar, Gujarat, 382355, India
| | - Rajanikant Patel
- Department of Product Development, Granules Pharmaceuticals Inc., 3701 Concorde Parkway, Chantilly, VA, 20151, USA
| | - Mohammad Fareed
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, P.O. Box 71666, 13713, Riyadh, Saudi Arabia
| | - Vivekanand A Kashid
- MABD Institute of Pharmaceutical Education and Research, Babhulgaon, Yeola, Nashik, India
| | - Bhupendra G Prajapati
- Department of Pharmaceutics and Pharmaceutical Technology, Shree S. K. Patel College of Pharmaceutical Education & Research, Ganpat University, Kherva, Mehsana, Gujarat, 384012, India.
- Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, 73000, Thailand.
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India.
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McDowall S, Bagda V, Hodgetts S, Mastaglia F, Li D. Controversies and insights into PTBP1-related astrocyte-neuron transdifferentiation: neuronal regeneration strategies for Parkinson's and Alzheimer's disease. Transl Neurodegener 2024; 13:59. [PMID: 39627843 PMCID: PMC11613593 DOI: 10.1186/s40035-024-00450-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 11/04/2024] [Indexed: 12/06/2024] Open
Abstract
Promising therapeutic strategies are being explored to replace or regenerate the neuronal populations that are lost in patients with neurodegenerative disorders. Several research groups have attempted direct reprogramming of astrocytes into neurons by manipulating the expression of polypyrimidine tract-binding protein 1 (PTBP1) and claimed putative converted neurons to be functional, which led to improved disease outcomes in animal models of several neurodegenerative disorders. However, a few other studies reported data that contradict these claims, raising doubt about whether PTBP1 suppression truly reprograms astrocytes into neurons and the therapeutic potential of this approach. This review discusses recent advances in regenerative therapeutics including stem cell transplantations for central nervous system disorders, with a particular focus on Parkinson's and Alzheimer's diseases. We also provide a perspective on this controversy by considering that astrocyte heterogeneity may be the key to understanding the discrepancy in published studies, and that certain subpopulations of these glial cells may be more readily converted into neurons.
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Affiliation(s)
- Simon McDowall
- Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia
- School of Human Sciences, The University of Western Australia, Crawley, Perth, WA, Australia
- Department of Anatomy and Department of Pathology, University of California San Francisco, San Francisco, CA, USA
| | - Vaishali Bagda
- Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia
| | - Stuart Hodgetts
- Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia
- School of Human Sciences, The University of Western Australia, Crawley, Perth, WA, Australia
| | - Frank Mastaglia
- Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia.
| | - Dunhui Li
- Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia.
- Centre for Molecular Medicine and Innovative Therapeutics, Health Futures Institute, Murdoch University, Murdoch, WA, Australia.
- Centre for Neuromuscular and Neurological Disorders, Nedlands, WA, Australia.
- Department of Neurology and Stephen and Denise Adams Center for Parkinson's Disease Research, Yale School of Medicine, New Haven, CT, USA.
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Antoon R, Overdevest N, Saleh AH, Keating A. Mesenchymal stromal cells as cancer promoters. Oncogene 2024; 43:3545-3555. [PMID: 39414984 PMCID: PMC11602730 DOI: 10.1038/s41388-024-03183-1] [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: 07/06/2024] [Revised: 09/12/2024] [Accepted: 09/26/2024] [Indexed: 10/18/2024]
Abstract
Mesenchymal stromal cells (MSCs) are important cellular constituents of tumor stroma that play an active role in tumor development. Complex interactions between MSCs and cancer promote tumor progression by creating a favorable milieu for tumor cell proliferation, angiogenesis, motility, invasion, and metastasis. The cellular heterogeneity, source of origin, diversity in isolation methods, culture techniques and model systems of MSCs, together with the different tumor subtypes, add to the complexity of MSC-tumor interactions. In this review, we discuss the mechanisms of MSC-mediated tumor promotion and evaluate cell-stromal interactions between cancer cells, MSCs, cells of the tumor microenvironment (TME), and the extracellular matrix (ECM). A more thorough understanding of tumor-MSC interactions is likely to lead to better cancer management.
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Affiliation(s)
| | | | - Amr H Saleh
- Faculty of Medicine, University of Alberta, Edmonton, AB, Canada.
- Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
| | - Armand Keating
- Krembil Research Institute, Toronto, ON, Canada.
- Princess Margaret Cancer Centre, Toronto, ON, Canada.
- University Health Network, Toronto, ON, Canada.
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Shah S, Ghosh D, Otsuka T, Laurencin CT. Classes of Stem Cells: From Biology to Engineering. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2024; 10:309-322. [PMID: 39387056 PMCID: PMC11463971 DOI: 10.1007/s40883-023-00317-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/30/2023] [Accepted: 08/16/2023] [Indexed: 10/12/2024]
Abstract
Purpose The majority of adult tissues are limited in self-repair and regeneration due to their poor intrinsic regenerative capacity. It is widely recognized that stem cells are present in almost all adult tissues, but the natural regeneration in adult mammals is not sufficient to recover function after injury or disease. Historically, 3 classes of stem cells have been defined: embryonic stem cells (ESCs), adult mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs). Here, we have defined a fourth fully engineered class: the synthetic artificial stem cell (SASC). This review aims to discuss the applications of these stem cell classes in musculoskeletal regenerative engineering. Method We screened articles in PubMed and bibliographic search using a combination of keywords. Relevant and high-cited articles were chosen for inclusion in this narrative review. Results In this review, we discuss the different classes of stem cells that are biologically derived (ESCs and MSCs) or semi-engineered/engineered (iPSCs, SASC). We also discuss the applications of these stem cell classes in musculoskeletal regenerative engineering. We further summarize the advantages and disadvantages of using each of the classes and how they impact the clinical translation of these therapies. Conclusion Each class of stem cells has advantages and disadvantages in preclinical and clinical settings. We also propose the engineered SASC class as a potentially disease-modifying therapy that harnesses the paracrine action of biologically derived stem cells to mimic regenerative potential. Lay Summary The majority of adult tissues are limited in self-repair and regeneration, even though stem cells are present in almost all adult tissues. Historically, 3 classes of stem cells have been defined: embryonic stem cells (ESCs), adult mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs). Here, we have defined a fourth, fully engineered class: the synthetic artificial stem cell (SASC). In this review, we discuss the applications of each of these stem cell classes in musculoskeletal regenerative engineering. We further summarize the advantages and disadvantages of using each of these classes and how they impact the clinical translation of these therapies.
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Affiliation(s)
- Shiv Shah
- The Cato T. Laurencin Institute for Regenerative Engineering, University of Connecticut, 263 Farmington Avenue, Farmington, CT 06030-3711, USA
- Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health, Farmington, CT, USA
- Department of Chemical and Biomolecular Engineering, University of Connecticut, Storrs, CT, USA
| | - Debolina Ghosh
- The Cato T. Laurencin Institute for Regenerative Engineering, University of Connecticut, 263 Farmington Avenue, Farmington, CT 06030-3711, USA
| | - Takayoshi Otsuka
- The Cato T. Laurencin Institute for Regenerative Engineering, University of Connecticut, 263 Farmington Avenue, Farmington, CT 06030-3711, USA
- Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health, Farmington, CT, USA
| | - Cato T. Laurencin
- The Cato T. Laurencin Institute for Regenerative Engineering, University of Connecticut, 263 Farmington Avenue, Farmington, CT 06030-3711, USA
- Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health, Farmington, CT, USA
- Department of Chemical and Biomolecular Engineering, University of Connecticut, Storrs, CT, USA
- Department of Orthopedic Surgery, University of Connecticut Health, Farmington, CT, USA
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT, USA
- Department of Materials Science and Engineering, University of Connecticut, Storrs, CT, USA
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Chen Y, Liang Z, Lai M. Targeting the devil: Strategies against cancer-associated fibroblasts in colorectal cancer. Transl Res 2024; 270:81-93. [PMID: 38614213 DOI: 10.1016/j.trsl.2024.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/06/2024] [Accepted: 04/10/2024] [Indexed: 04/15/2024]
Abstract
Cancer-associated fibroblasts (CAFs), as significant constituents of the tumor microenvironment (TME), play a pivotal role in the progression of cancers, including colorectal cancer (CRC). In this comprehensive review, we presented the origins and activation mechanisms of CAFs in CRC, elaborating on how CAFs drive tumor progression through their interactions with CRC cells, immune cells, vascular endothelial cells, and the extracellular matrix within the TME. We systematically outline the intricate web of interactions among CAFs, tumor cells, and other TME components, and based on this complex interplay, we summarize various therapeutic strategies designed to target CAFs in CRC. It is also essential to recognize that CAFs represent a highly heterogeneous group, encompassing various subtypes such as myofibroblastic CAF (myCAF), inflammatory CAF (iCAF), antigen-presenting CAF (apCAF), vessel-associated CAF (vCAF). Herein, we provide a summary of studies investigating the heterogeneity of CAFs in CRC and the characteristic expression patterns of each subtype. While the majority of CAFs contribute to the exacerbation of CRC malignancy, recent findings have revealed specific subtypes that exert inhibitory effects on CRC progression. Nevertheless, the comprehensive landscape of CAF heterogeneity still awaits exploration. We also highlight pivotal unanswered questions that need to be addressed before CAFs can be recognized as feasible targets for cancer treatment. In conclusion, the aim of our review is to elucidate the significance and challenges of advancing in-depth research on CAFs, while outlining the pathway to uncover the complex roles of CAFs in CRC and underscore their significant potential as therapeutic targets.
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Affiliation(s)
- Yuting Chen
- Department of Pathology, and Department of Pathology of Sir Run Run Shaw Hospital, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy of Chinese Academy of Medical Sciences (2019RU042), Zhejiang University School of Medicine, Hangzhou, 310058, China; Department of Pathology, State Key Laboratory of Complex Severe and Rare Disease, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Key Laboratory of Disease Proteomics of Zhejiang Province, Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Zhiyong Liang
- Department of Pathology, State Key Laboratory of Complex Severe and Rare Disease, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Maode Lai
- Department of Pathology, and Department of Pathology of Sir Run Run Shaw Hospital, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy of Chinese Academy of Medical Sciences (2019RU042), Zhejiang University School of Medicine, Hangzhou, 310058, China; Key Laboratory of Disease Proteomics of Zhejiang Province, Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
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Shimizu D, Yuge R, Kitadai Y, Ariyoshi M, Miyamoto R, Hiyama Y, Takigawa H, Urabe Y, Oka S. Pexidartinib and Immune Checkpoint Inhibitors Combine to Activate Tumor Immunity in a Murine Colorectal Cancer Model by Depleting M2 Macrophages Differentiated by Cancer-Associated Fibroblasts. Int J Mol Sci 2024; 25:7001. [PMID: 39000110 PMCID: PMC11241126 DOI: 10.3390/ijms25137001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 06/20/2024] [Accepted: 06/23/2024] [Indexed: 07/16/2024] Open
Abstract
Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are known to play supportive roles in tumor development and progression, but their interactions in colorectal cancer (CRC) remain unclear. Here, we investigated the effects of colon-cancer-derived CAFs on TAM differentiation, migration, and tumor immunity, both in vitro and in vivo. When co-cultured with monocytes, CAFs attracted monocytes and induced their differentiation into M2 macrophages. Immunohistology of surgically resected human CRC specimens and orthotopically transplanted mouse tumors revealed a correlation between numbers of CAFs and numbers of M2 macrophages. In a mouse model of CRC orthotopic transplantation, treatment with an inhibitor of the colony-stimulating factor-1 receptor (PLX3397) depleted M2 macrophages and increased CD8-positive T cells infiltrating the tumor nest. While this treatment had a minor effect on tumor growth, combining PLX3397 with anti-PD-1 antibody significantly reduced tumor growth. RNA-seq following combination therapy showed activation of tumor immunity. In summary, CAFs are involved in the induction and mobilization of M2 macrophage differentiation in the CRC tumor immune microenvironment, and the combination of cancer immunotherapy and PLX3397 may represent a novel therapeutic option for CRC.
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Affiliation(s)
- Daisuke Shimizu
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-0037, Japan
| | - Ryo Yuge
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-0037, Japan
| | - Yuki Kitadai
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-0037, Japan
| | - Misa Ariyoshi
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-0037, Japan
| | - Ryo Miyamoto
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-0037, Japan
| | - Yuichi Hiyama
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-0037, Japan
| | - Hidehiko Takigawa
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-0037, Japan
| | - Yuji Urabe
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-0037, Japan
| | - Shiro Oka
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-0037, Japan
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Miyamoto R, Takigawa H, Yuge R, Shimizu D, Ariyoshi M, Otani R, Tsuboi A, Tanaka H, Yamashita K, Hiyama Y, Urabe Y, Ishikawa A, Sentani K, Oka S. Analysis of anti-tumor effect and mechanism of GLS1 inhibitor CB-839 in colorectal cancer using a stroma-abundant tumor model. Exp Mol Pathol 2024; 137:104896. [PMID: 38703552 DOI: 10.1016/j.yexmp.2024.104896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 03/01/2024] [Accepted: 04/18/2024] [Indexed: 05/06/2024]
Abstract
BACKGROUND Glutaminase 1 (GLS1), a key enzyme in glutamine metabolism in cancer cells, acts as a tumor promoter and could be a potential therapeutic target. CB-839, a GLS1-specific inhibitor, was developed recently. Herein, we aimed to elucidate the anti-tumor effects and mechanism of action of CB-839 in colorectal cancer (CRC). METHODS Using the UCSC Xena public database, we evaluated GLS1 expression in various cancers. Immunostaining for GLS1 was performed on 154 surgically resected human CRC specimens. Subsequently, we examined the GLS1 mRNA expression levels in eight CRC cell lines and evaluated the association between GLS1 expression and CB-839 efficacy. To create a reproducible CRC model with abundant stroma and an allogeneic immune response, we co-transplanted CT26 and stem cells into BALB/c mice and treated them with CB-839. Finally, RNA sequencing of mouse tumors was performed. RESULTS Database analysis showed higher GLS1 expression in CRC tissues than in normal colon tissues. Clinical samples from 114 of the 154 patients with CRC showed positive GLS1 expression. GLS1 expression in clinical CRC tissues correlated with vascular invasion. CB-839 treatment inhibited cancer cell proliferation depending on GLS1 expression in vitro and inhibited tumor growth and metastasis in the CRC mouse model. RNA sequencing revealed that CB-839 treatment inhibited stromal activation, tumor growth, migration, and angiogenesis. These findings were validated through in vitro and in vivo experiments and clinical specimen analysis. CONCLUSIONS GLS1 expression in CRC plays important roles in tumor progression. CB-839 has inhibitory effects on cancer proliferation and the tumor microenvironment.
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Affiliation(s)
- Ryo Miyamoto
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hidehiko Takigawa
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
| | - Ryo Yuge
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Daisuke Shimizu
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Misa Ariyoshi
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Rina Otani
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Akiyoshi Tsuboi
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hidenori Tanaka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Ken Yamashita
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuichi Hiyama
- Clinical Research Center in Hiroshima, Hiroshima University Hospital, Hiroshima, Japan
| | - Yuji Urabe
- Department of Gastrointestinal Endoscopy and Medicine, Hiroshima University Hospital, Hiroshima, Japan
| | - Akira Ishikawa
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuhiro Sentani
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shiro Oka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Summers BS, Thomas Broome S, Pang TWR, Mundell HD, Koh Belic N, Tom NC, Ng ML, Yap M, Sen MK, Sedaghat S, Weible MW, Castorina A, Lim CK, Lovelace MD, Brew BJ. A Review of the Evidence for Tryptophan and the Kynurenine Pathway as a Regulator of Stem Cell Niches in Health and Disease. Int J Tryptophan Res 2024; 17:11786469241248287. [PMID: 38757094 PMCID: PMC11097742 DOI: 10.1177/11786469241248287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 04/03/2024] [Indexed: 05/18/2024] Open
Abstract
Stem cells are ubiquitously found in various tissues and organs in the body, and underpin the body's ability to repair itself following injury or disease initiation, though repair can sometimes be compromised. Understanding how stem cells are produced, and functional signaling systems between different niches is critical to understanding the potential use of stem cells in regenerative medicine. In this context, this review considers kynurenine pathway (KP) metabolism in multipotent adult progenitor cells, embryonic, haematopoietic, neural, cancer, cardiac and induced pluripotent stem cells, endothelial progenitor cells, and mesenchymal stromal cells. The KP is the major enzymatic pathway for sequentially catabolising the essential amino acid tryptophan (TRP), resulting in key metabolites including kynurenine, kynurenic acid, and quinolinic acid (QUIN). QUIN metabolism transitions into the adjoining de novo pathway for nicotinamide adenine dinucleotide (NAD) production, a critical cofactor in many fundamental cellular biochemical pathways. How stem cells uptake and utilise TRP varies between different species and stem cell types, because of their expression of transporters and responses to inflammatory cytokines. Several KP metabolites are physiologically active, with either beneficial or detrimental outcomes, and evidence of this is presented relating to several stem cell types, which is important as they may exert a significant impact on surrounding differentiated cells, particularly if they metabolise or secrete metabolites differently. Interferon-gamma (IFN-γ) in mesenchymal stromal cells, for instance, highly upregulates rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO-1), initiating TRP depletion and production of metabolites including kynurenine/kynurenic acid, known agonists of the Aryl hydrocarbon receptor (AhR) transcription factor. AhR transcriptionally regulates an immunosuppressive phenotype, making them attractive for regenerative therapy. We also draw attention to important gaps in knowledge for future studies, which will underpin future application for stem cell-based cellular therapies or optimising drugs which can modulate the KP in innate stem cell populations, for disease treatment.
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Affiliation(s)
- Benjamin Sebastian Summers
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia
| | - Sarah Thomas Broome
- Faculty of Science, Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, University of Technology Sydney, NSW, Australia
| | | | - Hamish D Mundell
- Faculty of Medicine and Health, New South Wales Brain Tissue Resource Centre, School of Medical Sciences, Charles Perkins Centre, University of Sydney, NSW, Australia
| | - Naomi Koh Belic
- School of Life Sciences, University of Technology, Sydney, NSW, Australia
| | - Nicole C Tom
- Formerly of the Department of Physiology, University of Sydney, NSW, Australia
| | - Mei Li Ng
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Maylin Yap
- Formerly of the Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Monokesh K Sen
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- School of Medicine, Western Sydney University, NSW, Australia
- Faculty of Medicine and Health, School of Medical Sciences, Charles Perkins Centre, The University of Sydney, NSW, Australia
| | - Sara Sedaghat
- Montreal Neurological Institute, McGill University, Montreal, QC, Canada
| | - Michael W Weible
- School of Environment and Science, Griffith University, Brisbane, QLD, Australia
- Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia
| | - Alessandro Castorina
- Faculty of Science, Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, University of Technology Sydney, NSW, Australia
| | - Chai K Lim
- Faculty of Medicine, Macquarie University, Sydney, NSW, Australia
| | - Michael D Lovelace
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia
| | - Bruce J Brew
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia
- Departments of Neurology and Immunology, St. Vincent’s Hospital, Sydney, NSW, Australia
- University of Notre Dame, Darlinghurst, Sydney, NSW, Australia
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Park J, Park SA, Kim YS, Kim D, Shin S, Lee SH, Jeun SS, Chung YJ, Ahn S. Intratumoral IL-12 delivery via mesenchymal stem cells combined with PD-1 blockade leads to long-term antitumor immunity in a mouse glioblastoma model. Biomed Pharmacother 2024; 173:115790. [PMID: 38431436 DOI: 10.1016/j.biopha.2023.115790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/18/2023] [Accepted: 10/26/2023] [Indexed: 03/05/2024] Open
Abstract
BACKGROUND Although PD-1 blockade is effective for treating several types of cancer, the efficacy of this agent in glioblastoma is largely limited. To overcome non-responders and the immunosuppressive tumor microenvironment, combinational immunotherapeutic strategies with anti-PD-1 need to be considered. Here, we developed IL-12-secreting mesenchymal stem cells (MSC_IL-12) with glioblastoma tropism and evaluated the therapeutic effects of anti-PD-1, MSC_IL-12, and their combination against glioblastoma. METHODS Therapeutic responses were evaluated using an immunocompetent mouse orthotopic model. Tumor-infiltrating lymphocytes (TILs) were analyzed using immunofluorescent imaging. Single-cell transcriptome was obtained from mouse brains after treatments. RESULTS Anti-PD-1 and MSC_IL-12 showed complete tumor remission in 25.0% (4/16) and 23.1% (3/13) of glioblastoma-implanted mice, respectively, and their combination yielded synergistic antitumor efficacy indicated by 50.0% (6/12) of complete tumor remission. Analyses of TILs revealed that anti-PD-1 increased CD8+ T cells, while MSC_IL-12 led to infiltration of CD4+ T cells and NK cells. Both therapies reduced frequencies of Tregs. All these aspects observed in each monotherapy group were superimposed in the combination group. Notably, no tumor growth was observed upon rechallenge in cured mice, indicating long-term immunity against glioblastoma provoked by the therapies. Single-cell RNA-seq data confirmed these results and revealed that the combined treatment led to immune-favorable tumor microenvironment-CD4+, CD8+ T cells, effector memory T cells, and activated microglia were increased, whereas exhausted T cells, Tregs, and M2 polarized microglia were reduced. CONCLUSION Anti-PD-1 and MSC_IL-12 monotherapies show long-term therapeutic responses, and their combination further enhances antitumor efficacy against glioblastoma via inducing immune-favorable tumor microenvironment.
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Affiliation(s)
- Junseong Park
- Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Soon A Park
- Department of Bio medicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Department of Neurosurgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yoon-Seob Kim
- Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Dokyeong Kim
- Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Department of Bio medicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sun Shin
- Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sug Hyung Lee
- Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sin-Soo Jeun
- Department of Neurosurgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yeun-Jun Chung
- Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Department of Bio medicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
| | - Stephen Ahn
- Department of Neurosurgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
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Lu Z, Miao X, Zhang C, Sun B, Skardal A, Atala A, Ai S, Gong J, Hao Y, Zhao J, Dai K. An osteosarcoma-on-a-chip model for studying osteosarcoma matrix-cell interactions and drug responses. Bioact Mater 2024; 34:1-16. [PMID: 38173844 PMCID: PMC10761322 DOI: 10.1016/j.bioactmat.2023.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/15/2023] [Accepted: 12/05/2023] [Indexed: 01/05/2024] Open
Abstract
Marrow niches in osteosarcoma (OS) are a specialized microenvironment that is essential for the maintenance and regulation of OS cells. However, existing animal xenograft models are plagued by variability, complexity, and high cost. Herein, we used a decellularized osteosarcoma extracellular matrix (dOsEM) loaded with extracellular vesicles from human bone marrow-derived stem cells (hBMSC-EVs) and OS cells as a bioink to construct a micro-osteosarcoma (micro-OS) through 3D printing. The micro-OS was further combined with a microfluidic system to develop into an OS-on-a-chip (OOC) with a built-in recirculating perfusion system. The OOC system successfully integrated bone marrow niches, cell‒cell and cell-matrix crosstalk, and circulation, allowing a more accurate representation of OS characteristics in vivo. Moreover, the OOC system may serve as a valuable research platform for studying OS biological mechanisms compared with traditional xenograft models and is expected to enable precise and rapid evaluation and consequently more effective and comprehensive treatments for OS.
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Affiliation(s)
- Zuyan Lu
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
| | - XiangWan Miao
- Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
| | - Chenyu Zhang
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Binbin Sun
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Aleksander Skardal
- Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA
| | - Anthony Atala
- Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
| | - Songtao Ai
- Department of Radiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - JiaNing Gong
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Yongqiang Hao
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Clinical and Translational Research Center for 3D Printing Technology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Zhao
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal System, Shanghai, China
| | - Kerong Dai
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Clinical and Translational Research Center for 3D Printing Technology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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12
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Riaz F, Zhang J, Pan F. Forces at play: exploring factors affecting the cancer metastasis. Front Immunol 2024; 15:1274474. [PMID: 38361941 PMCID: PMC10867181 DOI: 10.3389/fimmu.2024.1274474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 01/19/2024] [Indexed: 02/17/2024] Open
Abstract
Metastatic disease, a leading and lethal indication of deaths associated with tumors, results from the dissemination of metastatic tumor cells from the site of primary origin to a distant organ. Dispersion of metastatic cells during the development of tumors at distant organs leads to failure to comply with conventional treatments, ultimately instigating abrupt tissue homeostasis and organ failure. Increasing evidence indicates that the tumor microenvironment (TME) is a crucial factor in cancer progression and the process of metastatic tumor development at secondary sites. TME comprises several factors contributing to the initiation and progression of the metastatic cascade. Among these, various cell types in TME, such as mesenchymal stem cells (MSCs), lymphatic endothelial cells (LECs), cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), T cells, and tumor-associated macrophages (TAMs), are significant players participating in cancer metastasis. Besides, various other factors, such as extracellular matrix (ECM), gut microbiota, circadian rhythm, and hypoxia, also shape the TME and impact the metastatic cascade. A thorough understanding of the functions of TME components in tumor progression and metastasis is necessary to discover new therapeutic strategies targeting the metastatic tumor cells and TME. Therefore, we reviewed these pivotal TME components and highlighted the background knowledge on how these cell types and disrupted components of TME influence the metastatic cascade and establish the premetastatic niche. This review will help researchers identify these altered components' molecular patterns and design an optimized, targeted therapy to treat solid tumors and restrict metastatic cascade.
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Affiliation(s)
- Farooq Riaz
- Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen, China
| | - Jing Zhang
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Fan Pan
- Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen, China
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Taeb S, Rostamzadeh D, Mafi S, Mofatteh M, Zarrabi A, Hushmandi K, Safari A, Khodamoradi E, Najafi M. Update on Mesenchymal Stem Cells: A Crucial Player in Cancer Immunotherapy. Curr Mol Med 2024; 24:98-113. [PMID: 36573062 DOI: 10.2174/1566524023666221226143814] [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: 05/17/2022] [Revised: 10/17/2022] [Accepted: 10/17/2022] [Indexed: 12/28/2022]
Abstract
The idea of cancer immunotherapy has spread, and it has made tremendous progress with the advancement of new technology. Immunotherapy, which serves to assist the natural defenses of the body in eradicating cancerous cells, is a remarkable achievement that has revolutionized both cancer research and cancer treatments. Currently, the use of stem cells in immunotherapy is widespread and shares a special characteristic, including cancer cell migration, bioactive component release, and immunosuppressive activity. In the context of cancer, mesenchymal stem cells (MSCs) are rapidly being identified as vital stromal regulators of tumor progression. MSCs therapy has been implicated in treating a wide range of diseases, including bone damage, autoimmune diseases, and particularly hematopoietic abnormalities, providing stem cell-based therapy with an extra dimension. Moreover, the implication of MSCs does not have ethical concerns, and the complications known in pluripotent and totipotent stem cells are less common in MSCs. MSCs have a lot of distinctive characteristics that, when coupled, make them excellent for cellular-based immunotherapy and as vehicles for gene and drug delivery in a variety of inflammations and malignancies. MSCs can migrate to the inflammatory site and exert immunomodulatory responses via cell-to-cell contacts with lymphocytes by generating soluble substances. In the current review, we discuss the most recent research on the immunological characteristics of MSCs, their use as immunomodulatory carriers, techniques for approving MSCs to adjust their immunological contour, and their usages as vehicles for delivering therapeutic as well as drugs and genes engineered to destroy tumor cells.
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Affiliation(s)
- Shahram Taeb
- Department of Radiology, School of Paramedical Sciences, Guilan University of Medical Sciences, Rasht, Iran
| | - Davoud Rostamzadeh
- Department of Clinical Biochemistry, Yasuj University of Medical Sciences, Yasuj, Iran
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Sahar Mafi
- Department of Clinical Biochemistry, Yasuj University of Medical Sciences, Yasuj, Iran
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Mohammad Mofatteh
- Sir William Dunn School of Pathology, Medical Sciences Division, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom
- Lincoln College, University of Oxford, Turl Street, Oxford OX1 3DR, United Kingdom
| | - Ali Zarrabi
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, Istanbul, Turkey
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul, Turkey
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Arash Safari
- Department of Radiology, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ehsan Khodamoradi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Wang H, Cai G, Yu F, Li D, Wang C, Ma D, Han X, Chen J, Wang C, He J. Changes in the small noncoding RNA transcriptome in osteosarcoma cells. J Orthop Surg Res 2023; 18:898. [PMID: 38001513 PMCID: PMC10675919 DOI: 10.1186/s13018-023-04362-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
BACKGROUND Osteosarcoma has the highest incidence among bone malignant tumors and mainly occurs in adolescents and the elderly, but the pathological mechanism is still unclear, which makes early diagnosis and treatment very difficult. Bone marrow mesenchymal stem cells (BMSCs) are considered to be one of the sources of osteosarcoma cells. Therefore, a full understanding of the gene expression differences between BMSCs and osteosarcoma cells is very important to explore the pathogenesis of osteosarcoma and facilitate the early diagnosis and treatment of osteosarcoma. Small noncoding RNAs (sncRNAs) are a class of RNAs that do not encode proteins but directly play biological functions at the RNA level. SncRNAs mainly include Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), repeat RNAs and microRNAs (miRNAs). METHODS In this study, we compared the expression of sncRNAs in BMSCs and osteosarcoma cells by high-throughput sequencing and qPCR and looked for differentially expressed sncRNAs. CCK-8, clone formation and transwell assay were used to detect the effect of sncRNA in MG63 cells. RESULTS We found that 66 piRNAs were significantly upregulated and 70 piRNAs were significantly downregulated in MG63 cells. As for snoRNAs, 71 snoRNAs were significantly upregulated and 117 snoRNAs were significantly downregulated in MG63 cells. As for snRNAs, 35 snRNAs were significantly upregulated and 17 snRNAs were significantly downregulated in MG63 cells. As for repeat RNAs, 6 repeat RNAs were significantly upregulated and 7 repeat RNAs were significantly downregulated in MG63 cells. As for miRNAs, 326 miRNAs were significantly upregulated and 281 miRNAs were significantly downregulated in MG63 cells. Overexpression of piRNA DQ596225, snoRNA ENST00000364830.2, snRNA ENST00000410533.1 and miRNA hsa-miR-369-5p inhibited the proliferation and migration of MG63 cells. CONCLUSIONS Our results provide a theoretical basis for the pathogenesis, early diagnosis and treatment of osteosarcoma.
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Affiliation(s)
- Hui Wang
- Department of Orthopedic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, People's Republic of China
| | - Guiquan Cai
- Department of Orthopedic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, People's Republic of China
| | - Fengbin Yu
- Department of Orthopaedics, The 72nd Group Army Hospital of PLA, Huzhou, 313000, Zhejiang, People's Republic of China
| | - De Li
- Department of Orthopedic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, People's Republic of China
| | - Chenglong Wang
- Department of Orthopedic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, People's Republic of China
| | - Ding Ma
- Department of Orthopedic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, People's Republic of China
| | - Xiuguo Han
- Department of Orthopedic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, People's Republic of China
| | - Jiajia Chen
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Chuandong Wang
- Department of Orthopedic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, People's Republic of China.
| | - Jiye He
- Department of Orthopedic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, People's Republic of China.
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15
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Babu B, Stoltz SA, Mittal A, Pawar S, Kolanthai E, Coathup M, Seal S. Inorganic Nanoparticles as Radiosensitizers for Cancer Treatment. NANOMATERIALS (BASEL, SWITZERLAND) 2023; 13:2873. [PMID: 37947718 PMCID: PMC10647410 DOI: 10.3390/nano13212873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 10/25/2023] [Accepted: 10/27/2023] [Indexed: 11/12/2023]
Abstract
Nanotechnology has expanded what can be achieved in our approach to cancer treatment. The ability to produce and engineer functional nanoparticle formulations to elicit higher incidences of tumor cell radiolysis has resulted in substantial improvements in cancer cell eradication while also permitting multi-modal biomedical functionalities. These radiosensitive nanomaterials utilize material characteristics, such as radio-blocking/absorbing high-Z atomic number elements, to mediate localized effects from therapeutic irradiation. These materials thereby allow subsequent scattered or emitted radiation to produce direct (e.g., damage to genetic materials) or indirect (e.g., protein oxidation, reactive oxygen species formation) damage to tumor cells. Using nanomaterials that activate under certain physiologic conditions, such as the tumor microenvironment, can selectively target tumor cells. These characteristics, combined with biological interactions that can target the tumor environment, allow for localized radio-sensitization while mitigating damage to healthy cells. This review explores the various nanomaterial formulations utilized in cancer radiosensitivity research. Emphasis on inorganic nanomaterials showcases the specific material characteristics that enable higher incidences of radiation while ensuring localized cancer targeting based on tumor microenvironment activation. The aim of this review is to guide future research in cancer radiosensitization using nanomaterial formulations and to detail common approaches to its treatment, as well as their relations to commonly implemented radiotherapy techniques.
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Affiliation(s)
- Balaashwin Babu
- Advanced Materials Processing and Analysis Center, Department of Materials Science and Engineering, University of Central Florida, Orlando, FL 32826, USA; (B.B.); (S.A.S.); (A.M.); (S.P.); (E.K.)
| | - Samantha Archer Stoltz
- Advanced Materials Processing and Analysis Center, Department of Materials Science and Engineering, University of Central Florida, Orlando, FL 32826, USA; (B.B.); (S.A.S.); (A.M.); (S.P.); (E.K.)
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
| | - Agastya Mittal
- Advanced Materials Processing and Analysis Center, Department of Materials Science and Engineering, University of Central Florida, Orlando, FL 32826, USA; (B.B.); (S.A.S.); (A.M.); (S.P.); (E.K.)
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
| | - Shreya Pawar
- Advanced Materials Processing and Analysis Center, Department of Materials Science and Engineering, University of Central Florida, Orlando, FL 32826, USA; (B.B.); (S.A.S.); (A.M.); (S.P.); (E.K.)
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
| | - Elayaraja Kolanthai
- Advanced Materials Processing and Analysis Center, Department of Materials Science and Engineering, University of Central Florida, Orlando, FL 32826, USA; (B.B.); (S.A.S.); (A.M.); (S.P.); (E.K.)
| | - Melanie Coathup
- Biionix Cluster, University of Central Florida, Orlando, FL 32827, USA;
- College of Medicine, University of Central Florida, Orlando, FL 32827, USA
| | - Sudipta Seal
- Advanced Materials Processing and Analysis Center, Department of Materials Science and Engineering, University of Central Florida, Orlando, FL 32826, USA; (B.B.); (S.A.S.); (A.M.); (S.P.); (E.K.)
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
- College of Medicine, University of Central Florida, Orlando, FL 32827, USA
- Nanoscience Technology Center, University of Central Florida, Orlando, FL, USA
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Qi C, Shi H, Fan M, Chen W, Yao H, Jiang C, Meng L, Pang S, Lin R. Microvesicles from bone marrow-derived mesenchymal stem cells promote Helicobacter pylori-associated gastric cancer progression by transferring thrombospondin-2. Cell Commun Signal 2023; 21:274. [PMID: 37798762 PMCID: PMC10552243 DOI: 10.1186/s12964-023-01127-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 04/09/2023] [Indexed: 10/07/2023] Open
Abstract
BACKGROUND Our previous study found that bone marrow-derived mesenchymal stem cells (BMSCs) promote Helicobacter pylori (H pylori)-associated gastric cancer (GC) progression by secreting thrombospondin-2 (THBS2). Extracellular vesicles (EVs) are important carriers for intercellular communication, and EVs secreted by BMSCs have been shown to be closely related to tumor development. The aim of this study was to investigate whether BMSC-derived microvesicles (MVs, a main type of EV) play a role in H. pylori-associated GC by transferring THBS2. METHODS BMSCs and THBS2-deficient BMSCs were treated with or without the supernatant of H. pylori for 12 h at a multiplicity of infection of 50, and their EVs were collected. Then, the effects of BMSC-derived MVs and THBS2-deficient BMSC-derived MVs on the GC cell line MGC-803 were assessed by in vitro proliferation, migration, and invasion assays. In addition, a subcutaneous xenograft tumor model, a nude mouse intraperitoneal metastasis model, and a tail vein injection metastasis model were constructed to evaluate the effects of BMSC-derived MVs and THBS2-deficient BMSC-derived MVs on GC development and metastasis in vivo. RESULTS BMSC-derived MVs could be readily internalized by MGC-803 cells. BMSC-derived MVs after H. pylori treatment significantly promoted their proliferation, migration and invasion in vitro (all P < 0.05) and promoted tumor development and metastasis in a subcutaneous xenograft tumor model, a nude mouse intraperitoneal metastasis model, and a tail vein injection metastasis model in vivo (all P < 0.05). The protein expression of THBS2 was significantly upregulated after H. pylori treatment in BMSC-derived MVs (P < 0.05). Depletion of the THBS2 gene reduces the tumor-promoting ability of BMSC-MVs in an H. pylori infection microenvironment both in vitro and in vivo. CONCLUSION Overall, these findings indicate that MVs derived from BMSCs can promote H. pylori-associated GC development and metastasis by delivering the THBS2 protein. Video Abstract.
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Affiliation(s)
- Cuihua Qi
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 4300222 China
- Department of Gastroenterology, The First Affiliated Hospital of Shihezi University, Shihezi, 832002 China
| | - Huiying Shi
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 4300222 China
| | - Mengke Fan
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 4300222 China
| | - Weigang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Shihezi University, Shihezi, 832002 China
| | - Hailing Yao
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 4300222 China
| | - Chen Jiang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 4300222 China
| | - Lingjun Meng
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 4300222 China
| | - Suya Pang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 4300222 China
| | - Rong Lin
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 4300222 China
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He X, Yao W, Zhu JD, Jin X, Liu XY, Zhang KJ, Zhao SL. Potent antitumor efficacy of human dental pulp stem cells armed with YSCH-01 oncolytic adenovirus. J Transl Med 2023; 21:688. [PMID: 37789452 PMCID: PMC10546667 DOI: 10.1186/s12967-023-04539-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 09/19/2023] [Indexed: 10/05/2023] Open
Abstract
BACKGROUND Systemic administration of oncolytic adenovirus for cancer therapy is still a challenge. Mesenchymal stem cells as cell carriers have gained increasing attention in drug delivery due to their excellent tumor tropism, immunosuppressive modulatory effects, and paracrine effects. However, the potential of human dental pulp stem cells (hDPSCs) loaded with oncolytic adenovirus for cancer biotherapy has not been investigated yet. METHODS The stemness of hDPSCs was characterized by FACS analysis and Alizarin red staining, Oil Red O staining, and immunofluorescence assays. The biological fitness of hDPSCs loaded with oncolytic adenovirus YSCH-01 was confirmed by virus infection with different dosages and cell viability CCK-8 assays. Additionally, the expression of CAR receptor in hDPSCs was detected by qPCR assay. Tumor tropism of hDPSC loaded with YSCH-01 in vitro and in vivo was investigated by Transwell assays and living tumor-bearing mice imaging technology and immunohistochemistry, Panoramic scanning of frozen section slices assay analysis. Furthermore, the antitumor efficacy was observed through the different routes of YSCH-01/hPDSCs administration in SW780 and SCC152 xenograft models. The direct tumor cell-killing effect of YSCH-01/hDPSCs in the co-culture system was studied, and the supernatant of YSCH-01/hDPSCs inhibited cell growth was further analyzed by CCK-8 assays. RESULTS hDPSCs were found to be susceptible to infection by a novel oncolytic adenovirus named YSCH-01 and were capable of transporting this virus to tumor sites at 1000 VP/cell infectious dosage in vitro and in vivo. Moreover, it was discovered that intraperitoneal injection of hDPSCs loaded with oncolytic adenovirus YSCH-01 exhibited potential anti-tumor effects in both SW780 and SCC152 xenograft models. The crucial role played by the supernatant secretome derived from hDPSCs loaded with YSCH-01 significantly exerted a specific anti-tumor effect without toxicity for normal cells, in both an active oncolytic virus and an exogenous protein-independent manner. Furthermore, the use of hDPSCs as a cell carrier significantly reduced the required dosage of virus delivery in vivo compared to other methods. CONCLUSIONS These findings highlight the promising clinical potential of hDPSCs as a novel cell carrier in the field of oncolytic virus-based anti-cancer therapy.
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Affiliation(s)
- Xu He
- Department of Stomatology, Huashan Hospital, Fudan University, 12 Urumqi Road, Jing'an District, Shanghai, 200040, China
| | - Wei Yao
- Shanghai Fengxian Stomatological Hospital, 189 Wanghe Road, Fengxian District, Shanghai, 201499, China
| | - Ji-Ding Zhu
- Shanghai Fengxian Stomatological Hospital, 189 Wanghe Road, Fengxian District, Shanghai, 201499, China
| | - Xin Jin
- Department of Stomatology, School of Medicine, Renji Hospital, Shanghai Jiaotong University, 160 Pujian Road, Pudong New Area, Shanghai, 200025, China
| | - Xin-Yuan Liu
- Academician Expert Workstation of Fengxian District, Shanghai Yuansong Biotechnology Limited Company, 1588 Huhang Road, Fengxian District, Shanghai, 201499, China
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, 320 Yueyang Road, Xuhui District, Shanghai, 200031, China
| | - Kang-Jian Zhang
- Academician Expert Workstation of Fengxian District, Shanghai Yuansong Biotechnology Limited Company, 1588 Huhang Road, Fengxian District, Shanghai, 201499, China.
- Institute of Smart Biomedical Materials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, 928 Second Avenue, Xiasha Higher Education Zone, Hangzhou, 310018, China.
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, 320 Yueyang Road, Xuhui District, Shanghai, 200031, China.
| | - Shou-Liang Zhao
- Department of Stomatology, Huashan Hospital, Fudan University, 12 Urumqi Road, Jing'an District, Shanghai, 200040, China.
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18
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Bormann D, Gugerell A, Ankersmit HJ, Mildner M. Therapeutic Application of Cell Secretomes in Cutaneous Wound Healing. J Invest Dermatol 2023; 143:893-912. [PMID: 37211377 DOI: 10.1016/j.jid.2023.02.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 02/02/2023] [Accepted: 02/10/2023] [Indexed: 05/23/2023]
Abstract
Although the application of stem cells to chronic wounds emerged as a candidate therapy in the previous century, the mechanism of action remains unclear. Recent evidence has implicated secreted paracrine factors in the regenerative properties of cell-based therapies. In the last two decades, considerable research advances involving the therapeutic potential of stem cell secretomes have expanded the scope of secretome-based therapies beyond stem cell populations. In this study, we review the modes of action of cell secretomes in wound healing, important preconditioning strategies for enhancing their therapeutic efficacy, and clinical trials on secretome-based wound healing.
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Affiliation(s)
- Daniel Bormann
- Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Alfred Gugerell
- Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Hendrik Jan Ankersmit
- Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Michael Mildner
- Department of Dermatology, Medical University of Vienna, Vienna, Austria.
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19
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Park J, Lee D, Shim JK, Yoon SJ, Moon JH, Kim EH, Chang JH, Lee SJ, Kang SG. Mesenchymal Stem-Like Cells Derived from the Ventricle More Effectively Enhance Invasiveness of Glioblastoma Than Those Derived from the Tumor. Yonsei Med J 2023; 64:157-166. [PMID: 36825341 PMCID: PMC9971438 DOI: 10.3349/ymj.2022.0430] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 01/02/2023] [Accepted: 01/05/2023] [Indexed: 02/15/2023] Open
Abstract
PURPOSE Glioblastoma (GBM) is one of the most lethal human tumors with a highly infiltrative phenotype. Our previous studies showed that GBM originates in the subventricular zone, and that tumor-derived mesenchymal stem-like cells (tMSLCs) promote the invasiveness of GBM tumorspheres (TSs). Here, we extend these studies in terms of ventricles using several types of GBM patient-derived cells. MATERIALS AND METHODS The invasiveness of GBM TSs and ventricle spheres (VSs) were quantified via collagen-based 3D invasion assays. Gene expression profiles were obtained from microarray data. A mouse orthotopic xenograft model was used for in vivo experiments. RESULTS After molecular and functional characterization of ventricle-derived mesenchymal stem-like cells (vMSLCs), we investigated the effects of these cells on the invasiveness of GBM TSs. We found that vMSLC-conditioned media (CM) significantly accelerated the invasiveness of GBM TSs and VSs, compared to the control and even tMSLC-CM. Transcriptome analyses revealed that vMSLC secreted significantly higher levels of several invasiveness-associated cytokines. Moreover, differentially expressed genes between vMSLCs and tMSLCs were enriched for migration, adhesion, and chemotaxis-related gene sets, providing a mechanistic basis for vMSLC-induced invasion of GBM TSs. In vivo experiments using a mouse orthotopic xenograft model confirmed vMSLC-induced increases in the invasiveness of GBM TSs. CONCLUSION Although vMSLCs are non-tumorigenic, this study adds to our understanding of how GBM cells acquire infiltrative features by vMSLCs, which are present in the region where GBM genesis originates.
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Affiliation(s)
- Junseong Park
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Dongkyu Lee
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Brain Tumor Translational Research Laboratory, Avison Biomedical Research Center, Yonsei University College of Medicine, Seoul, Korea
| | - Jin-Kyoung Shim
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Brain Tumor Translational Research Laboratory, Avison Biomedical Research Center, Yonsei University College of Medicine, Seoul, Korea
| | - Seon-Jin Yoon
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Department of Biochemistry and Molecular Biology, College of Medicine, Yonsei University, Seoul, Korea
| | - Ju Hyung Moon
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Eui Hyun Kim
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Brain Tumor Translational Research Laboratory, Avison Biomedical Research Center, Yonsei University College of Medicine, Seoul, Korea
| | - Jong Hee Chang
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Su-Jae Lee
- Fibrosis and Cancer Targeting Biotechnology, FNCT Biotech, Seoul, Korea
| | - Seok-Gu Kang
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Brain Tumor Translational Research Laboratory, Avison Biomedical Research Center, Yonsei University College of Medicine, Seoul, Korea
- Department of Medical Science, Yonsei University Graduate School, Seoul, Korea.
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20
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Ding W, Zhang K, Li Q, Xu L, Ma Y, Han F, Zhu L, Sun X. Advances in Understanding the Roles of Mesenchymal Stem Cells in Lung Cancer. Cell Reprogram 2023; 25:20-31. [PMID: 36594933 DOI: 10.1089/cell.2022.0133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Lung cancer is the most common and deadliest type of cancer worldwide. Research concerning lung cancer has made considerable progress in recent decades, but lung cancer remains the leading cause of malignancy-related mortality rate. Mesenchymal stem cells (MSCs) mainly exist in fat, umbilical cord blood, bone marrow, bone, and muscle. MSCs are a primary component of the tumor microenvironment (TME). Recent studies have shown that MSCs have roles in lung cancer-related proliferation, invasion, migration, and angiogenesis, but the underlying mechanisms are poorly understood. Because MSCs can migrate to the TME, there is increasing attention toward the use of MSCs in drugs or gene vectors for cancer treatment. This review summarizes the roles and effects of MSCs in lung cancer, while addressing clinical applications of MSCs in lung cancer treatment.
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Affiliation(s)
- Wenli Ding
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China.,Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China.,Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Kexin Zhang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China.,Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Qinying Li
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China.,Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Linfei Xu
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Yanhui Ma
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Fang Han
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China.,Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China.,Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Liang Zhu
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China.,Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Xiaodong Sun
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China.,Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
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21
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Zarubova J, Hasani-Sadrabadi MM, Norris SCP, Majedi FS, Xiao C, Kasko AM, Li S. Cell-Taxi: Mesenchymal Cells Carry and Transport Clusters of Cancer Cells. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2203515. [PMID: 36307906 PMCID: PMC9772300 DOI: 10.1002/smll.202203515] [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: 06/10/2022] [Revised: 09/09/2022] [Indexed: 06/16/2023]
Abstract
Cell clusters that collectively migrate from primary tumors appear to be far more potent in forming distant metastases than single cancer cells. A better understanding of the collective cell migration phenomenon and the involvement of various cell types during this process is needed. Here, an in vitro platform based on inverted-pyramidal microwells to follow and quantify the collective migration of hundreds of tumor cell clusters at once is developed. These results indicate that mesenchymal stromal cells (MSCs) or cancer-associated fibroblasts (CAFs) in the heterotypic tumor cell clusters may facilitate metastatic dissemination by transporting low-motile cancer cells in a Rac-dependent manner and that extracellular vesicles secreted by mesenchymal cells only play a minor role in this process. Furthermore, in vivo studies show that cancer cell spheroids containing MSCs or CAFs have faster spreading rates. These findings highlight the active role of co-traveling stromal cells in the collective migration of tumor cell clusters and may help in developing better-targeted therapies.
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Affiliation(s)
- Jana Zarubova
- Department of Bioengineering, University of California, 420 Westwood Plaza, 5121 Engineering V, Los Angeles, CA, 90095-1600, USA
- Department of Biomaterials and Tissue Engineering, Institute of Physiology of the Czech Academy of Sciences, Prague, 14220, Czech Republic
| | - Mohammad Mahdi Hasani-Sadrabadi
- Department of Bioengineering, University of California, 420 Westwood Plaza, 5121 Engineering V, Los Angeles, CA, 90095-1600, USA
| | - Sam C P Norris
- Department of Bioengineering, University of California, 420 Westwood Plaza, 5121 Engineering V, Los Angeles, CA, 90095-1600, USA
| | - Fatemeh Sadat Majedi
- Department of Bioengineering, University of California, 420 Westwood Plaza, 5121 Engineering V, Los Angeles, CA, 90095-1600, USA
| | - Crystal Xiao
- Department of Bioengineering, University of California, 420 Westwood Plaza, 5121 Engineering V, Los Angeles, CA, 90095-1600, USA
| | - Andrea M Kasko
- Department of Bioengineering, University of California, 420 Westwood Plaza, 5121 Engineering V, Los Angeles, CA, 90095-1600, USA
| | - Song Li
- Department of Bioengineering, University of California, 420 Westwood Plaza, 5121 Engineering V, Los Angeles, CA, 90095-1600, USA
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22
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Xue C, Gao Y, Li X, Zhang M, Yang Y, Han Q, Sun Z, Bai C, Zhao RC. Mesenchymal stem cells derived from adipose accelerate the progression of colon cancer by inducing a MT-CAFs phenotype via TRPC3/NF-KB axis. STEM CELL RESEARCH & THERAPY 2022; 13:335. [PMID: 35870973 PMCID: PMC9308187 DOI: 10.1186/s13287-022-03017-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 01/10/2022] [Indexed: 12/02/2022]
Abstract
Background There is increasing evidence that mesenchymal stem cells (MSCs) help shape the tumor microenvironment and promote tumor progression, and ion channels might play a critical role in this process. The objective of the present study was to explore the function and mechanism of MT-CAFs on progression of colon cancer. Methods Here, a gene chip was used for a general analysis of gene expression changes in MSC-transformed CAF cells (MT-CAFs). Bioinformatic tool and western blot screened out the ion channel protein TRPC3 with significantly increased expression, and identify the function through two-photon microscope. The progression of cancer was detected via MTS, transwell and Wound Healing. ELISA deected the secretion of inflammation factors. TRPC3/NF-KB axis was identified by western blot and immunofluorescence. Results TRPC3 can caused calcium influx, which further activated the NF-KB signaling pathway. Knockdown or inhibition of TRPC3 in MSCs significantly reduced the activation of NF-KB, and decreased the growth, migration, and invasion of MT-CAFs. After TRPC3 knockdown, the ability of MT- CAFs to promote tumor migration and invasion was impaired. Conversely, the upregulation of TRPC3 expression in MT-CAFs had the opposite effect. In vivo, TRPC3 expressed on MSCs also contributed to the tumorigenesis and progression of cancer cells. In addition, the Oncomine and GEPIA databases showed that TRPC3 expression is higher in colon cancer tissues compared with normal colon tissues, and was positively correlated with the expression of the CAF genes alpha-smooth muscle (α-SMA/ACTA2) and fibroblast activation protein Alpha. The disease-free survival of patients with positive TRPC3 expression in MSCs was significantly shorter than those with negative expression. Conclusions These results indicate that TRPC3 expressed on MT-CAFs plays a critical role in tumor progression via the NF-KB signaling pathway, and is correlated with poor prognosis in colon cancer patients. Therefore, TRPC3 may be a novel therapeutic target for the treatment of colon cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03017-5.
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23
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Sirithammajak S, Manochantr S, Tantrawatpan C, Tantikanlayaporn D, Kheolamai P. Human Mesenchymal Stem Cells Derived from the Placenta and Chorion Suppress the Proliferation while Enhancing the Migration of Human Breast Cancer Cells. Stem Cells Int 2022; 2022:4020845. [PMID: 36406002 PMCID: PMC9674426 DOI: 10.1155/2022/4020845] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 10/21/2022] [Accepted: 10/31/2022] [Indexed: 12/29/2023] Open
Abstract
BACKGROUND Breast cancer is the most frequently diagnosed malignancy among women, resulting from abnormal proliferation of mammary epithelial cells. The highly vascularized nature of breast tissue leads to a high incidence of breast cancer metastases, resulting in a poor survival rate. Previous studies suggest that human mesenchymal stem cells (hMSCs) play essential roles in the growth, metastasis, and drug responses of many cancers, including breast cancer. However, hMSCs from different sources may release different combinations of cytokines that affect breast cancer differently. METHODS In this study, we have isolated hMSCs from the placenta (PL-hMSCs) and the chorion (CH-hMSCs) and determined how these hMSCs affect the proliferation, migration, invasion, and gene expression of two human breast cancer cells, MCF-7 and MDA-MB-231, as well as the possible mechanisms underlying those effects. RESULTS The results showed that the soluble factors derived from PL-hMSCs and CH-hMSCs inhibited the proliferation of MCF-7 and MDA-MB-231 cells but increased the migration of MDA-MB-231 cells. The study of gene expression showed that PL-hMSCs and CH-hMSCs downregulated the expression levels of the protooncogene CyclinD1 while upregulating the expression levels of tumor suppressor genes, P16 and P21 in MCF-7 and MDA-MB-231 cells. Furthermore, hMSCs from both sources also increased the expression levels of MYC, SNAI1, and TWIST, which promote the epithelial-mesenchymal transition and migration of breast cancer cells in both cell lines. The functional study suggests that the suppressive effect of CH-hMSCs and PL-hMSCs on MCF-7 and MDA-MB231 cell proliferation was mediated, at least in part, through IFN-γ. CONCLUSIONS Our study suggests that CH-hMSCs and PL-hMSCs inhibited breast cancer cell proliferation by negatively regulating CYCLIND1 expression and upregulating the expression of the P16 and P21 genes. In contrast, hMSCs from both sources enhanced breast cancer cell migration, possibly by increasing the expression of MYC, SNAI1, and TWIST genes in those cells.
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Affiliation(s)
- Sarawut Sirithammajak
- Center of Excellence in Stem Cell Research and Innovation, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand
| | - Sirikul Manochantr
- Center of Excellence in Stem Cell Research and Innovation, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand
- Division of Cell Biology, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand
| | - Chairat Tantrawatpan
- Center of Excellence in Stem Cell Research and Innovation, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand
- Division of Cell Biology, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand
| | - Duangrat Tantikanlayaporn
- Center of Excellence in Stem Cell Research and Innovation, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand
- Division of Cell Biology, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand
| | - Pakpoom Kheolamai
- Center of Excellence in Stem Cell Research and Innovation, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand
- Division of Cell Biology, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand
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24
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Zhang M, Li X, Wu W, Gao J, Han Q, Sun Z, Zhao RC. Regorafenib induces the apoptosis of gastrointestinal cancer-associated fibroblasts by inhibiting AKT phosphorylation. Stem Cells Dev 2022; 31:383-394. [PMID: 35502476 DOI: 10.1089/scd.2022.0088] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs) are a key component of tumor microenvironment and are essential for tumorigenesis and development. Regorafenib is a multikinase inhibitor that targets CAFs and suppresses tumor growth. Here, we investigated the effects of regorafenib on gastrointestinal CAFs and the underlying molecular mechanisms. First, we established two in vivo tumor models, the cancer cell line HCT116 with or without mesenchymal stem cells (MSCs) and treated them with regorafenib. We found that the application of regorafenib potently impaired tumor growth, an effect that was more pronounced in tumors with a high stromal ratio, thus demonstrating that regorafenib can inhibit CAFs proliferation and induce CAFs apoptosis in vivo. Moreover, we showed that regorafenib affected macrophage infiltration by reducing the proportion of CAFs in tumors. Afterward, we induced MSCs into CAFs with exosomes to establish an in vitro model. Then, we used MTS and flow cytometry to detect the effects of regorafenib on the proliferation and apoptosis of CAFs, and Western blot to determine the expression level of apoptosis-related proteins. We found that regorafenib inhibited the proliferation of CAFs and induced the apoptosis of CAFs in vitro. Furthermore, Western blot results showed that regorafenib down-regulated the expression of B-cell lymphoma-2 (Bcl-2) and concurrently up-regulated the expression of Bcl-2-associated X (Bax), and regorafenib inhibited the phosphorylation pathway of AKT in CAFs. In conclusion, our results provide a model in which regorafenib induces CAFs apoptosis by inhibiting the phosphorylation of AKT, and regorafenib affects macrophage infiltration by reducing the proportion of CAFs in tumor tissues.
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Affiliation(s)
- Mingjia Zhang
- Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Basic Medical Sciences, 196536, Centre of Excellence in Tissue Engineering，Chinese Academy of Medical Sciences , Beijing, Beijing, China;
| | - Xuechun Li
- Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Basic Medical Sciences, 196536, Centre of Excellence in Tissue Engineering，Chinese Academy of Medical Sciences , Beijing, Beijing, China;
| | - Wenjing Wu
- Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Basic Medical Sciences, 196536, Centre of Excellence in Tissue Engineering，Chinese Academy of Medical Sciences , Beijing, Beijing, China;
| | - Jingxi Gao
- Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Basic Medical Sciences, 196536, Centre of Excellence in Tissue Engineering，Chinese Academy of Medical Sciences , Beijing, Beijing, China;
| | - Qin Han
- Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Basic Medical Sciences, 196536, Centre of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences, Beijing, Beijing, China;
| | - Zhao Sun
- Peking Union Medical College Hospital, 34732, Department of oncology, Dongcheng-qu, Beijing, China;
| | - Robert Chunhua Zhao
- Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Basic Medical Sciences, 196536, Centre of Excellence in Tissue Engineering，Chinese Academy of Medical Sciences , Beijing, Beijing, China.,Shanghai University, 34747, School of Life Sciences, Shanghai, Shanghai, China;
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25
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Quiroz-Reyes AG, González-Villarreal CA, Martínez-Rodriguez H, Said-Fernández S, Salinas-Carmona MC, Limón-Flores AY, Soto-Domínguez A, Padilla-Rivas G, Montes De Oca-Luna R, Islas JF, Garza-Treviño EN. A combined antitumor strategy of separately transduced mesenchymal stem cells with soluble TRAIL and IFNβ produces a synergistic activity in the reduction of lymphoma and mice survival enlargement. Mol Med Rep 2022; 25:206. [PMID: 35485288 PMCID: PMC9073847 DOI: 10.3892/mmr.2022.12722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 03/29/2022] [Indexed: 11/11/2022] Open
Abstract
As the understanding of cancer grows, new therapies have been proposed to improve the well-known limitations of current therapies, whose efficiency relies mostly on early detection, surgery and chemotherapy. Mesenchymal stem cells (MSCs) have been introduced as a promissory and effective therapy. This fact is due to several useful features of MSCs, such as their accessibility and easy culture and expansion in vitro, and their remarkable ability for ‘homing’ towards tumors, allowing MSCs to exert their anticancer effects directly into tumors. Additionally, MSCs offer the practicability of being genetically engineered to carry anticancer genes, increasing their specificity and efficacy for fighting tumors. In the present study, the antitumoral efficacy and post-implant survival of mice bearing lymphomas implanted intratumorally were determined using mouse bone marrow-derived (BM)-MSCs transduced with soluble TRAIL (sTRAIL), full length TRAIL (flTRAIL), or interferon β (IFNβ), naïve BM-MSCs, or combinations of these. The percentage of surviving mice was determined once all not-implanted mice succumbed. It was found that the percentage of surviving mice implanted with the combination of MSCs-sTRAIL and MSCs-IFN-β was 62.5%. Lymphoma model achieved 100% fatality in the non-treated group by day 41. On the other hand, the percentage of surviving mice implanted with MSCs-sTRAIL was 50% and with MSCs-INFβ 25%. All the aforementioned differences were statistically significant (P<0.05). In conclusion, all implants exhibited tumor size reduction, growth delay, or apparent tumor clearance. MSCs proved to be effective anti-lymphoma agents; additionally, the combination of soluble TRAIL and IFN-β resulted in the most effective antitumor and life enlarging treatment, showing an additive antitumoral effect compared with individual treatments.
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Affiliation(s)
- Adriana G Quiroz-Reyes
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Autonomous University of Nuevo Leon, Monterrey, Nuevo León 64460, Mexico
| | - Carlos A González-Villarreal
- Laboratory of Molecular Genetics, Department of Basic Sciences, University of Monterrey, Monterrey, Nuevo León 66238, Mexico
| | - Herminia Martínez-Rodriguez
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Autonomous University of Nuevo Leon, Monterrey, Nuevo León 64460, Mexico
| | - Salvador Said-Fernández
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Autonomous University of Nuevo Leon, Monterrey, Nuevo León 64460, Mexico
| | - Mario César Salinas-Carmona
- Department of Immunology, Faculty of Medicine, Autonomous University of Nuevo Leon, Monterrey, Nuevo León 64460, Mexico
| | - Alberto Y Limón-Flores
- Department of Immunology, Faculty of Medicine, Autonomous University of Nuevo Leon, Monterrey, Nuevo León 64460, Mexico
| | - Adolfo Soto-Domínguez
- Department of Histology, Faculty of Medicine, Autonomous University of Nuevo Leon, Monterrey, Nuevo León 64460, Mexico
| | - Gerardo Padilla-Rivas
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Autonomous University of Nuevo Leon, Monterrey, Nuevo León 64460, Mexico
| | - Roberto Montes De Oca-Luna
- Department of Histology, Faculty of Medicine, Autonomous University of Nuevo Leon, Monterrey, Nuevo León 64460, Mexico
| | - Jose F Islas
- Department of Histology, Faculty of Medicine, Autonomous University of Nuevo Leon, Monterrey, Nuevo León 64460, Mexico
| | - Elsa N Garza-Treviño
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Autonomous University of Nuevo Leon, Monterrey, Nuevo León 64460, Mexico
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26
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Goïta AA, Guenot D. Colorectal Cancer: The Contribution of CXCL12 and Its Receptors CXCR4 and CXCR7. Cancers (Basel) 2022; 14:1810. [PMID: 35406582 PMCID: PMC8997717 DOI: 10.3390/cancers14071810] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/22/2022] [Accepted: 03/29/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is one of the most common cancers, and diagnosis at late metastatic stages is the main cause of death related to this cancer. This progression to metastasis is complex and involves different molecules such as the chemokine CXCL12 and its two receptors CXCR4 and CXCR7. The high expression of receptors in CRC is often associated with a poor prognosis and aggressiveness of the tumor. The interaction of CXCL12 and its receptors activates signaling pathways that induce chemotaxis, proliferation, migration, and cell invasion. To this end, receptor inhibitors were developed, and their use in preclinical and clinical studies is ongoing. This review provides an overview of studies involving CXCR4 and CXCR7 in CRC with an update on their targeting in anti-cancer therapies.
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Affiliation(s)
| | - Dominique Guenot
- INSERM U1113/Unistra, IRFAC—Interface de Recherche Fondamentale et Appliquée en Cancérologie, 67200 Strasbourg, France;
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27
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Liu X, Zhao G, Huo X, Wang Y, Tigyi G, Zhu BM, Yue J, Zhang W. Adipose-Derived Stem Cells Facilitate Ovarian Tumor Growth and Metastasis by Promoting Epithelial to Mesenchymal Transition Through Activating the TGF-β Pathway. Front Oncol 2022; 11:756011. [PMID: 35004276 PMCID: PMC8727693 DOI: 10.3389/fonc.2021.756011] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 11/29/2021] [Indexed: 02/05/2023] Open
Abstract
Adipose-derived stem cells (ADSC) are multipotent mesenchymal stem cells derived from adipose tissues and are capable of differentiating into multiple cell types in the tumor microenvironment (TME). The roles of ADSC in ovarian cancer (OC) metastasis are still not well defined. To understand whether ADSC contributes to ovarian tumor metastasis, we examined epithelial to mesenchymal transition (EMT) markers in OC cells following the treatment of the ADSC-conditioned medium (ADSC-CM). ADSC-CM promotes EMT in OC cells. Functionally, ADSC-CM promotes OC cell proliferation, survival, migration, and invasion. We further demonstrated that ADSC-CM induced EMT via TGF-β growth factor secretion from ADSC and the ensuing activation of the TGF-β pathway. ADSC-CM-induced EMT in OC cells was reversible by the TGF-β inhibitor SB431542 treatment. Using an orthotopic OC mouse model, we also provide the experimental evidence that ADSC contributes to ovarian tumor growth and metastasis by promoting EMT through activating the TGF-β pathway. Taken together, our data indicate that targeting ADSC using the TGF-β inhibitor has the therapeutic potential in blocking the EMT and OC metastasis.
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Affiliation(s)
- Xiaowu Liu
- Department of Urology, The First Affiliated Hospital of China Medical University, Shenyang, China.,Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Guannan Zhao
- Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States.,Center for Cancer Research, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Xueyun Huo
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yaohong Wang
- Department of Pathology, Immunology, and Microbiology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Gabor Tigyi
- Department of Physiology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Bing-Mei Zhu
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Junming Yue
- Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States.,Center for Cancer Research, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Wenjing Zhang
- Department of Genetics, Genomics & Informatics, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
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Rosner M, Hengstschläger M. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:26-34. [PMID: 35641164 PMCID: PMC8895487 DOI: 10.1093/stcltm/szab003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 09/12/2021] [Indexed: 12/03/2022] Open
Abstract
It is the hope of clinicians and patients alike that stem cell-based therapeutic products will increasingly become applicable remedies for many diseases and injuries. Whereas some multipotent stem cells are already routinely used in regenerative medicine, the efficacious and safe clinical translation of pluripotent stem cells is still hampered by their inherent immunogenicity and tumorigenicity. In addition, stem cells harbor the paracrine potential to affect the behavior of cells in their microenvironment. On the one hand, this property can mediate advantageous supportive effects on the overall therapeutic concept. However, in the last years, it became evident that both, multipotent and pluripotent stem cells, are capable of inducing adjacent cells to become motile. Not only in the context of tumor development but generally, deregulated mobilization and uncontrolled navigation of patient’s cells can have deleterious consequences for the therapeutic outcome. A more comprehensive understanding of this ubiquitous stem cell feature could allow its proper clinical handling and could thereby constitute an important building block for the further development of safe therapies.
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Affiliation(s)
- Margit Rosner
- Institute of Medical Genetics, Center of Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria
| | - Markus Hengstschläger
- Institute of Medical Genetics, Center of Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria
- Corresponding author: Markus Hengstschläger, PhD, Professor, Institute of Medical Genetics, Medical University of Vienna, Währinger Strasse 10, 1090 Vienna, Austria. Tel: +43 1 40160 56500; Fax: +43 1 40160 956501;
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29
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Inoue T, Hayashi Y, Tsujii Y, Yoshii S, Sakatani A, Kimura K, Uema R, Kato M, Saiki H, Shinzaki S, Iijima H, Takehara T. Suppression of autophagy promotes fibroblast activation in p53-deficient colorectal cancer cells. Sci Rep 2021; 11:19524. [PMID: 34593902 PMCID: PMC8484348 DOI: 10.1038/s41598-021-98865-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 09/15/2021] [Indexed: 12/15/2022] Open
Abstract
Deficiency of p53 in cancer cells activates the transformation of normal tissue fibroblasts into carcinoma-associated fibroblasts; this promotes tumor progression through a variety of mechanisms in the tumor microenvironment. The role of autophagy in carcinoma-associated fibroblasts in tumor progression has not been elucidated. We aimed to clarify the significance of autophagy in fibroblasts, focusing on the TP53 status in co-cultured human colorectal cancer cell lines (TP53-wild-type colon cancer, HCT116; TP53-mutant colon cancer, HT29; fibroblast, CCD-18Co) in vitro. Autophagy in fibroblasts was significantly suppressed in association with ACTA2, CXCL12, TGFβ1, VEGFA, FGF2, and PDGFRA mRNA levels, when co-cultured with p53-deficient HCT116sh p53 cells. Exosomes isolated from the culture media of HCT116sh p53 cells significantly suppressed autophagy in fibroblasts via inhibition of ATG2B. Exosomes derived from TP53-mutant HT29 cells also suppressed autophagy in fibroblasts. miR-4534, extracted from the exosomes of HCT116sh p53 cells, suppressed ATG2B in fibroblasts. In conclusion, a loss of p53 function in colon cancer cells promotes the activation of surrounding fibroblasts through the suppression of autophagy. Exosomal miRNAs derived from cancer cells may play a pivotal role in the suppression of autophagy.
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Affiliation(s)
- Takanori Inoue
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yoshito Hayashi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yoshiki Tsujii
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Shunsuke Yoshii
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Akihiko Sakatani
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Keiichi Kimura
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ryotaro Uema
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Minoru Kato
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hirotsugu Saiki
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Shinichiro Shinzaki
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hideki Iijima
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
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Chandra Jena B, Sarkar S, Rout L, Mandal M. The transformation of cancer-associated fibroblasts: Current perspectives on the role of TGF-β in CAF mediated tumor progression and therapeutic resistance. Cancer Lett 2021; 520:222-232. [PMID: 34363903 DOI: 10.1016/j.canlet.2021.08.002] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/16/2021] [Accepted: 08/01/2021] [Indexed: 12/12/2022]
Abstract
Over the last few years, the Transforming growth factor- β (TGF-β) has been significantly considered as an effective and ubiquitous mediator of cell growth. The cytokine, TGF-β is being increasingly recognized as the most potent inducer of cancer cell initiation, differentiation, migration as well as progression through both the SMAD-dependent and independent pathways. There is growing evidence that supports the role of secretory cytokine TGF-β as a crucial mediator of tumor-stroma crosstalk. Contextually, the CAFs are the prominent component of tumor stroma that helps in tumor progression and onset of chemoresistance. The interplay between the CAFs and the tumor cells through the paracrine signals is facilitated by cytokine TGF-β to induce the malignant progression. Here in this review, we have dissected the most recent advancements in understanding the mechanisms of TGF-β induced CAF activation, their multiple origins, and most importantly their role in conferring chemoresistance. Considering the pivotal role of TGF-β in tumor perogression and associated stemness, it is one the proven clinical targets We have also included the clinical trials going on, targeting the TGF-β and CAFs crosstalk with the tumor cells. Ultimately, we have underscored some of the outstanding issues that must be deciphered with utmost importance to unravel the successful strategies of anti-cancer therapies.
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Affiliation(s)
- Bikash Chandra Jena
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India
| | - Siddik Sarkar
- CSIR-Indian Institue of Chemical Biology, Translational Research Unit of Excellence, Kolkata, West Bengal, India
| | - Lipsa Rout
- Department of Chemistry, Institute of Technical Education and Research, Siksha'O'Anusandhan Deemed to be University, Bhubaneswar, Odisha, India
| | - Mahitosh Mandal
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India.
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31
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Zhang W, Torres-Rojas C, Yue J, Zhu BM. Adipose-derived stem cells in ovarian cancer progression, metastasis, and chemoresistance. Exp Biol Med (Maywood) 2021; 246:1810-1815. [PMID: 34229470 DOI: 10.1177/15353702211023846] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Ovarian cancer is the deadliest gynecological malignancy due to its symptomless early stage, metastasis, and high recurrence rate. The tumor microenvironment contributes to the ovarian cancer progression, metastasis, and chemoresistance. Adipose-derived stem cell in the tumor microenvironment of ovarian cancer, as a key player, interacts with ovarian cancer cells to form the cancer-associated fibroblasts and cancer-associated adipocytes, and secretes soluble factors to activate tumor cell signaling, which can promote ovarian cancer metastasis and chemoresistance. We summarize in this review the recent progress in the studies of interactions between adipose-derived stem cell and ovarian cancer, thus, to provide some insight for ovarian cancer therapy through targeting adipose-derived stem cell.
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Affiliation(s)
- Wenjing Zhang
- Department of Genetics, Genomics & Informatics, College of Medicine, the University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Carolina Torres-Rojas
- Department of Genetics, Genomics & Informatics, College of Medicine, the University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Junming Yue
- Department of Pathology and Laboratory Medicine, College of Medicine, the University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Bing-Mei Zhu
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
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32
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Sharma U, Medina-Saenz K, Miller PC, Troness B, Spartz A, Sandoval-Leon A, Parke DN, Seagroves TN, Lippman ME, El-Ashry D. Heterotypic clustering of circulating tumor cells and circulating cancer-associated fibroblasts facilitates breast cancer metastasis. Breast Cancer Res Treat 2021; 189:63-80. [PMID: 34216317 DOI: 10.1007/s10549-021-06299-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 06/12/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND Cancer-associated fibroblasts (CAFs) are recruited to the tumor microenvironment (TME) and are critical drivers of breast cancer (BC) malignancy. Circulating tumor cells (CTCs) travel through hematogenous routes to establish metastases. CTCs circulate both individually and, more rarely, in clusters with other cell types. Clusters of CTCs have higher metastatic potential than single CTCs. Previously, we identified circulating CAFs (cCAFs) in patients with BC and found that while healthy donors had no CTCs or cCAFs, both were present in most Stage IV patients. cCAFs circulate individually, as cCAF-cCAF homotypic clusters, and in heterotypic clusters with CTCs. METHODS In this study, we evaluate CTCs, cCAFs, and heterotypic cCAF-CTC clusters in patients with stage I-IV BC. We evaluate the association of heterotypic clusters with BC disease progression and metastasis in a spontaneous mouse model. Using previously established primary BC and CAF cell lines, we examine the metastatic propensity of heterotypic cCAF-CTC clusters in orthotopic and tail vein xenograft mouse models of BC. Using an in vitro clustering assay, we determine factors that may be involved in clustering between CAF and BC cells. RESULTS We report that the dissemination of CTCs, cCAFs, and clusters is an early event in BC progression, and we find these clusters in all clinical stages of BC. Furthermore, cCAFs-CTC heterotypic clusters have a higher metastatic potential than homotypic CTC clusters in vivo. We also demonstrate that the adhesion and stemness marker CD44, found on a subset of CTCs and CAF cells, is involved in heterotypic clustering of these cells. CONCLUSION We identify a novel subset of circulating tumor cell clusters that are enriched with stromal CAF cells in BC patient blood and preclinical mouse models of BC metastasis. Our data suggest that clustering of CTCs with cCAFs augments their metastatic potential and that CD44 might be an important mediator of heterotypic clustering of cCAFs and BC cells.
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Affiliation(s)
- Utsav Sharma
- Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.,Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC, USA
| | - Kelsie Medina-Saenz
- Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC, USA
| | - Philip C Miller
- Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC, USA
| | - Benjamin Troness
- Department of Laboratory Medicine and Pathology, Masonic Cancer Center, University of Minnesota, 2231 6th St. SE Minneapolis, Minneapolis, MN, 55455, USA
| | - Angela Spartz
- Department of Laboratory Medicine and Pathology, Masonic Cancer Center, University of Minnesota, 2231 6th St. SE Minneapolis, Minneapolis, MN, 55455, USA
| | - Ana Sandoval-Leon
- Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
| | - Deanna N Parke
- Department of Pathology, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Tiffany N Seagroves
- Department of Pathology, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Marc E Lippman
- Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC, USA
| | - Dorraya El-Ashry
- Department of Laboratory Medicine and Pathology, Masonic Cancer Center, University of Minnesota, 2231 6th St. SE Minneapolis, Minneapolis, MN, 55455, USA.
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Kostadinova M, Mourdjeva M. Potential of Mesenchymal Stem Cells in Anti-Cancer Therapies. Curr Stem Cell Res Ther 2021; 15:482-491. [PMID: 32148199 DOI: 10.2174/1574888x15666200310171547] [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] [Received: 08/21/2019] [Revised: 09/27/2019] [Accepted: 11/12/2019] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem/stromal cells (MSCs) are localized throughout the adult body as a small population in the stroma of the tissue concerned. In injury, tissue damage, or tumor formation, they are activated and leave their niche to migrate to the site of injury, where they release a plethora of growth factors, cytokines, and other bioactive molecules. With the accumulation of data about the interaction between MSCs and tumor cells, the dualistic role of MSCs remains unclear. However, a large number of studies have demonstrated the natural anti-tumor properties inherent in MSCs, so this is the basis for intensive research for new methods using MSCs as a tool to suppress cancer cell development. This review focuses specifically on advanced approaches in modifying MSCs to become a powerful, precision- targeted tool for killing cancer cells, but not normal healthy cells. Suppression of tumor growth by MSCs can be accomplished by inducing apoptosis or cell cycle arrest, suppressing tumor angiogenesis, or blocking mechanisms mediating metastasis. In addition, the chemosensitivity of cancer cells may be increased so that the dose of the chemotherapeutic agent used could be significantly reduced.
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Affiliation(s)
- Milena Kostadinova
- Department of Molecular Immunology, Institute of Biology and Immunology of Reproduction "Acad. Kiril Bratanov", Bulgarian Academy of Sciences, 73 Tsarigradsko Shose, 1113 Sofia, Bulgaria
| | - Milena Mourdjeva
- Department of Molecular Immunology, Institute of Biology and Immunology of Reproduction "Acad. Kiril Bratanov", Bulgarian Academy of Sciences, 73 Tsarigradsko Shose, 1113 Sofia, Bulgaria
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34
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He R, Han C, Li Y, Qian W, Hou X. Cancer-Preventive Role of Bone Marrow-Derived Mesenchymal Stem Cells on Colitis-Associated Colorectal Cancer: Roles of Gut Microbiota Involved. Front Cell Dev Biol 2021; 9:642948. [PMID: 34150751 PMCID: PMC8212064 DOI: 10.3389/fcell.2021.642948] [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: 12/17/2020] [Accepted: 02/26/2021] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) treatment showed promising results in inflammatory bowel disease in both rodent models and patients. Nevertheless, previous studies conducted conflicting results on preclinical tumor models treated with MSCs concerning their influence on tumor initiation and progression. This study is designed to demonstrate the role of bone marrow-derived MSCs and the potential mechanism in the colitis-associated colon cancer (CAC) model. METHODS Bone marrow-derived MSCs were isolated from green fluorescent protein-transgenic mice, cultured, and identified by flow cytometry. Azoxymethane and dextran sulfate sodium were administrated to establish the CAC mouse model, and MSCs were infused intraperitoneally once per week. The mice were weighed weekly, and colon length, tumor number, and average tumor size were assessed after the mice were killed. MSC localization was detected by immunofluorescence staining; tumor cell proliferation and apoptosis were measured by immunohistochemistry staining of Ki-67 and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay, respectively. The colonic tumor tissues were isolated for RNA-seq, and fecal samples were collected for 16S ribosomal RNA sequencing of the microbiome. RESULTS After injection intraperitoneally, MSCs migrated to the intestine and inhibited the initiation of colitis-associated colorectal cancer. This inhibition effect was marked by less weight loss, longer colon length, and reduced tumor numbers. Moreover, MSCs reduced tumor cell proliferation and induced tumor cell apoptosis. Furthermore, MSCs could inhibit chronic inflammation assessed by RNA-sequencing and promote gut microbiome normalization detected by 16S ribosomal RNA sequencing. CONCLUSION The results proved that MSCs could migrate to the colon, inhibit chronic inflammation, and regulate gut microbiome dysbiosis to suppress the development of CAC.
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Affiliation(s)
| | | | | | | | - Xiaohua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Naito T, Yuge R, Kitadai Y, Takigawa H, Higashi Y, Kuwai T, Kuraoka K, Tanaka S, Chayama K. Mesenchymal stem cells induce tumor stroma formation and epithelial‑mesenchymal transition through SPARC expression in colorectal cancer. Oncol Rep 2021; 45:104. [PMID: 33907853 PMCID: PMC8072806 DOI: 10.3892/or.2021.8055] [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: 10/25/2020] [Accepted: 02/09/2021] [Indexed: 12/18/2022] Open
Abstract
Tumor-stroma interactions serve a crucial role in the development of colorectal cancer (CRC), in which secreted protein acidic and rich in cysteine (SPARC) has been implicated. Due to interactions between cancer and stromal cells [mesenchymal stem cells (MSCs)], SPARC gene expression is markedly upregulated in CRC cells. The present study investigated the role of SPARC in CRC development and its potential as a biomarker. Specifically, the present study examined the association between SPARC expression and clinicopathological characteristics in 42 cases of CRC. SPARC expression in cancer cells was associated with T grade, N grade (TNM classification), stage and poor prognosis. Furthermore, the area of fibroblast-activating protein-positive staining around the cancer cells was increased in SPARC-positive compared with SPARC-negative cases. Proliferation and wound healing assays in SPARC-silenced KM12SM cells [short hairpin RNA SPARC (shSPARC)], the reduced SPARC expression of which was demonstrated by reverse transcription-quantitative PCR, revealed that the proliferative and migratory capacity of shSPARC cells did not differ from that of wild-type (WT) cells. However, it was markedly reduced when co-cultured with MSCs. Furthermore, in vivo, immunohistological analysis and RNA sequencing were conducted in an orthotopic implanted mouse model. Tumor growth and lymph node metastasis were markedly suppressed in shSPARC-transplanted tumors compared with WT-transplanted tumors, with a more marked suppression observed following shSPARC co-transplantation with MSCs. Immunohistological examination further revealed that the stromal reaction and epithelial-mesenchymal transition (EMT) were markedly suppressed in tumors co-transplanted with shSPARC and MSCs, and these results were consistent with RNA sequencing using RNA extracted from orthotopic tumors. Overall, these results suggested that SPARC expression in CRC cells is dependent on the interaction between cancer cells and stromal cells to induce EMT and promote stromal formation in the tumor microenvironment, suggesting its suitability as a novel target molecule for CRC treatment.
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Affiliation(s)
- Toshikatsu Naito
- Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima 734‑8551, Japan
| | - Ryo Yuge
- Department of Endoscopy and Medicine, Hiroshima University, Hiroshima 734‑8551, Japan
| | - Yasuhiko Kitadai
- Department of Health Science, Prefectural University of Hiroshima, Hiroshima 734‑8558, Japan
| | - Hidehiko Takigawa
- Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima 734‑8551, Japan
| | - Yukihito Higashi
- Department of Cardiovascular Physiology and Medicine, Hiroshima University, Hiroshima 734‑8551, Japan
| | - Toshio Kuwai
- Department of Gastroenterology, National Hospital Organization Kure Medical Center, Hiroshima 737‑0023, Japan
| | - Kazuya Kuraoka
- Department of Pathology, National Hospital Organization Kure Medical Center, Hiroshima 737‑0023, Japan
| | - Shinji Tanaka
- Department of Endoscopy and Medicine, Hiroshima University, Hiroshima 734‑8551, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima 734‑8551, Japan
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Lim EJ, Kim S, Oh Y, Suh Y, Kaushik N, Lee JH, Lee HJ, Kim MJ, Park MJ, Kim RK, Cha J, Kim SH, Shim JK, Choi J, Chang JH, Hong YK, Huh YM, Kim P, Kang SG, Lee SJ. Crosstalk between GBM cells and mesenchymal stemlike cells promotes the invasiveness of GBM through the C5a/p38/ZEB1 axis. Neuro Oncol 2021; 22:1452-1462. [PMID: 32179921 DOI: 10.1093/neuonc/noaa064] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Mesenchymal stemlike cells (MSLCs) have been detected in many types of cancer including brain tumors and have received attention as stromal cells in the tumor microenvironment. However, the cellular mechanisms underlying their participation in cancer progression remain largely unexplored. The aim of this study was to determine whether MSLCs have a tumorigenic role in brain tumors. METHODS To figure out molecular and cellular mechanisms in glioma invasion, we have cultured glioma with MSLCs in a co-culture system. RESULTS Here, we show that MSLCs in human glioblastoma (GBM) secrete complement component C5a, which is known for its role as a complement factor. MSLC-secreted C5a increases expression of zinc finger E-box-binding homeobox 1 (ZEB1) via activation of p38 mitogen-activated protein kinase (MAPK) in GBM cells, thereby enhancing the invasion of GBM cells into parenchymal brain tissue. CONCLUSION Our results reveal a mechanism by which MSLCs undergo crosstalk with GBM cells through the C5a/p38 MAPK/ZEB1 signaling loop and act as a booster in GBM progression. KEY POINTS 1. MSLCs activate p38 MAPK-ZEB1 signaling in GBM cells through C5a in a paracrine manner, thereby boosting the invasiveness of GBM cells in the tumor microenvironment.2. Neutralizing of C5a could be a potential therapeutic target for GBM by inhibition of mesenchymal phenotype.
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Affiliation(s)
- Eun-Jung Lim
- Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.,Memorial Sloan Kettering, Cancer Center, New York, New York, USA
| | - Seungmo Kim
- Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea
| | - Yoonjee Oh
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
| | - Yongjoon Suh
- Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea
| | - Neha Kaushik
- Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea
| | - Ji-Hyun Lee
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hae-June Lee
- Division of Radiation Effect, Korea Institute of Radiological & Medical Sciences, Seoul, Korea
| | - Min-Jung Kim
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Myung-Jin Park
- Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Rae-Kwon Kim
- Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon, Korea
| | - Junghwa Cha
- College of Pharmacy, Yonsei Institute of Pharmaceutical Science, Yonsei University, Incheon, Korea
| | - Se Hoon Kim
- Department of Pathology, Severance Hospital, Yonsei University, College of Medicine, Seoul, Korea
| | - Jin-Kyoung Shim
- Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea
| | - Junjeong Choi
- College of Pharmacy, Yonsei Institute of Pharmaceutical Science, Yonsei University, Incheon, Korea.,KAIST Institute for Health Science and Technology, Daejeon, Korea
| | - Jong Hee Chang
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Yong Kil Hong
- Department of Neurosurgery, Seoul St Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Yong Min Huh
- Department of Radiology, Severance Hospital, Yonsei University, College of Medicine, Seoul, Korea
| | - Pilnam Kim
- Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.,KAIST Institute for Health Science and Technology, Daejeon, Korea
| | - Seok-Gu Kang
- Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea
| | - Su-Jae Lee
- Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea
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Zhuang WZ, Lin YH, Su LJ, Wu MS, Jeng HY, Chang HC, Huang YH, Ling TY. Mesenchymal stem/stromal cell-based therapy: mechanism, systemic safety and biodistribution for precision clinical applications. J Biomed Sci 2021; 28:28. [PMID: 33849537 PMCID: PMC8043779 DOI: 10.1186/s12929-021-00725-7] [Citation(s) in RCA: 144] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 04/07/2021] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are a promising resource for cell-based therapy because of their high immunomodulation ability, tropism towards inflamed and injured tissues, and their easy access and isolation. Currently, there are more than 1200 registered MSC clinical trials globally. However, a lack of standardized methods to characterize cell safety, efficacy, and biodistribution dramatically hinders the progress of MSC utility in clinical practice. In this review, we summarize the current state of MSC-based cell therapy, focusing on the systemic safety and biodistribution of MSCs. MSC-associated risks of tumor initiation and promotion and the underlying mechanisms of these risks are discussed. In addition, MSC biodistribution methodology and the pharmacokinetics and pharmacodynamics of cell therapies are addressed. Better understanding of the systemic safety and biodistribution of MSCs will facilitate future clinical applications of precision medicine using stem cells.
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Affiliation(s)
- Wei-Zhan Zhuang
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan
| | - Yi-Heng Lin
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, 10041, Taiwan.,Department of Obstetrics and Gynecology, National Taiwan University Hospital Yunlin Branch, Yunlin, 64041, Taiwan
| | - Long-Jyun Su
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, 106, Taiwan
| | - Meng-Shiue Wu
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10617, Taiwan
| | - Han-Yin Jeng
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan
| | - Huan-Cheng Chang
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, 106, Taiwan.,Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei, 106, Taiwan
| | - Yen-Hua Huang
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. .,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. .,TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. .,International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan. .,Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, 11031, Taiwan. .,Comprehensive Cancer Center of Taipei Medical University, Taipei, 11031, Taiwan. .,The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
| | - Thai-Yen Ling
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10617, Taiwan. .,Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, 100, Taiwan.
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Aslam N, Abusharieh E, Abuarqoub D, Alhattab D, Jafar H, Alshaer W, Masad RJ, Awidi AS. An In Vitro Comparison of Anti-Tumoral Potential of Wharton's Jelly and Bone Marrow Mesenchymal Stem Cells Exhibited by Cell Cycle Arrest in Glioma Cells (U87MG). Pathol Oncol Res 2021; 27:584710. [PMID: 34257532 PMCID: PMC8262206 DOI: 10.3389/pore.2021.584710] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 02/12/2021] [Indexed: 12/18/2022]
Abstract
The therapeutic potential of mesenchymal stem cells (MSCs) for various malignancies is currently under investigation due to their unique properties. However, many discrepancies regarding their anti-tumoral or pro-tumoral properties have raised uncertainty about their application for anti-cancer therapies. To investigate, if the anti-tumoral or pro-tumoral properties are subjective to the type of MSCs under different experimental conditions we set out these experiments. Three treatments namely cell lysates (CL), serum-free conditioned media and FBS conditioned media (FBSCM) from each of Wharton’s Jelly MSCs and Bone Marrow-MSCs were applied to evaluate the anti-tumoral or pro-tumoral effect on the glioma cells (U87MG). The functional analysis included; Morphological evaluation, proliferation and migration potential, cell cycle analysis, and apoptosis for glioma cells. The fibroblast cell line was added to investigate the stimulatory or inhibitory effect of treatments on the proliferation of the normal cell. We found that cell lysates induced a generalized inhibitory effect on the proliferation of the glioma cells and the fibroblasts from both types of MSCs. Similarly, both types of conditioned media from two types of MSCs exerted the same inhibitory effect on the proliferation of the glioma cells. However, the effect of two types of conditioned media on the proliferation of fibroblasts was stimulatory from BM-MSCs and variable from WJ-MSCs. Moreover, all three treatments exerted a likewise inhibitory effect on the migration potential of the glioma cells. Furthermore, we found that the cell cycle was arrested significantly at the G1 phase after treating cells with conditioned media which may have led to inhibit the proliferative and migratory abilities of the glioma cells (U87MG). We conclude that cell extracts of MSCs in the form of secretome can induce specific anti-tumoral properties in serum-free conditions for the glioma cells particularly the WJ-MSCs and the effect is mediated by the cell cycle arrest at the G1 phase.
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Affiliation(s)
- Nazneen Aslam
- Cell Therapy Center, The University of Jordan, Amman, Jordan
| | - Elham Abusharieh
- Cell Therapy Center, The University of Jordan, Amman, Jordan.,Department of Pharmaceutical science, Faculty of Pharmacy, The University of Jordan, Amman, Jordan
| | - Duaa Abuarqoub
- Cell Therapy Center, The University of Jordan, Amman, Jordan.,Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra. Amman, Jordan
| | - Dana Alhattab
- Cell Therapy Center, The University of Jordan, Amman, Jordan.,Laboratory for Nanomedicine, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Hanan Jafar
- Cell Therapy Center, The University of Jordan, Amman, Jordan.,Department of Anatomy and Histology, School of Medicine, The University of Jordan, Amman, Jordan
| | - Walhan Alshaer
- Cell Therapy Center, The University of Jordan, Amman, Jordan
| | - Razan J Masad
- Cell Therapy Center, The University of Jordan, Amman, Jordan
| | - Abdalla S Awidi
- Cell Therapy Center, The University of Jordan, Amman, Jordan.,Department of Medicine, School of Medicine, The University of Jordan, Amman, Jordan.,Department of Hematology and Oncology, Jordan University Hospital, The University of Jordan, Amman, Jordan.,Department of Hematology and Oncology, The University of Jordan, Amman, Jordan
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Ma X, Chen J, Liu J, Xu B, Liang X, Yang X, Feng Y, Liang X, Liu J. IL-8/CXCR2 mediates tropism of human bone marrow-derived mesenchymal stem cells toward CD133 + /CD44 + Colon cancer stem cells. J Cell Physiol 2021; 236:3114-3128. [PMID: 33078417 DOI: 10.1002/jcp.30080] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 09/09/2020] [Accepted: 09/14/2020] [Indexed: 12/15/2022]
Abstract
In cancer treatment, the most attractive feature of mesenchymal stem cells (MSCs) is it's homing to tumor tissues. MSC is an important part of the "colon cancer stem cell niche", but little research has been done on the tropism of human MSCs toward colon cancer stem cells (CCSCs). In this study, we first compared the effects of three tissue-derived MSCs (bone marrow, adipose tissue, and placenta) in vivo on colon tumor xenograft growth. Then, we analyzed the tropism of bone marrow-derived MSCs (BMSCs) toward normal intestinal epithelial cells (NCM460), parental colon cancer cells, CD133- /CD44-, and CD133+ /CD44+ colon cancer cells in vitro. Microarray analysis and in vitro experiments explored the mechanism of mediating the homing of BMSCs toward CCSCs. Compared with the parental and CD133- /CD44- colon cancer cells, CD133+ /CD44+ cells have a stronger ability to recruit BMSCs. In addition, BMSCs were significantly transformed into cancer-associated fibroblasts after being recruited by CCSCs. After coculture of BMSCs and CCSCs, the expression of interleukin (IL)-6, IL-8, IL-32, and CCL20 was significantly increased. Compared with parental strains, CD133- /CD44- cells, and NCM460, BMSC secreted significantly more IL-8 after coculture with CD133+ /CD44+ cells. Low concentration of IL-8 peptide inhibitors (100 ng/ml) and CXC receptor 2 (CXCR2) inhibitors have little effect on the migration of BMSCs, but can effectively weaken CCSC stemness and promote dormant CSCs in the coculture system to re-enter into the cell cycle. The endogenous IL-8 knockout in BMSCs or BMSCs loaded with IL-8 and/or CXCR2 inhibitors will make the therapy of BMSC targeting CCSCs function at its best.
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Affiliation(s)
- Xiaoying Ma
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Jingyun Chen
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Jiajun Liu
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Baixue Xu
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Xinyu Liang
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Xiaotong Yang
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Yun Feng
- Department of Respiratory and Critical Care Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xin Liang
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Jianwen Liu
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
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Wang MY, Wang YX, Li-Ling J, Xie HQ. Adult Stem Cell Therapy for Premature Ovarian Failure: From Bench to Bedside. TISSUE ENGINEERING PART B-REVIEWS 2021; 28:63-78. [PMID: 33427039 DOI: 10.1089/ten.teb.2020.0205] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Premature ovarian failure (POF) is a devastating condition for women of childbearing age with serious health consequences, including distress, infertility, osteoporosis, autoimmune disorders, ischemic heart disease, and increased mortality. In addition to the mainstay estrogen therapy, stem cell therapy has been tested as the result of rapid progress in cell biology and reprogramming research. We hereby provide a review for the latest research and issues related with stem cell-based therapy for POF, and provide a commentary on various methods for enhancing its effect. Large amount of animal studies have demonstrated an extensive benefit of stem cells for failed ovarian recovering. As shown by such studies, stem cell therapy can result in recovery of hormonal levels, follicular activation, ovarian angiogenesis, and functional restoration. Meanwhile, a study of molecular pathways revealed that the function of stem cells mainly depends on their paracrine actions, which can produce multiple factors for the promotion of ovarian angiogenesis and regulation of cellular functions. Nevertheless, studies using disease models also revealed certain drawbacks. Clinical trials have shown that menstrual cycle and even pregnancy may occur in POF patients following transplantation of stem cells, although the limitations, including inadequate number of cases and space for the improvement of transplantation methodology. Only with its safety and effect get substantial improvement through laboratory experiments and clinical trials, can stem cell therapy really bring benefits to more patients. Additionally, effective pretreatment and appropriate transplantation methods for stem cells are also required. Taken together, stem cell therapy has shown a great potential for the reversal of POF and is stepping from bench to bedside. Impact statement Premature ovarian failure (POF) is a devastating condition with serious clinical consequences. The purpose of this review was to summarize the current status of stem cell therapy for POF. Considering the diversity of cell types and functions, a rigorous review is required for the guidance for further research into this field. Meanwhile, the challenges and prospect for clinical application of stem cell treatment, methodological improvements, and innovations are addressed.
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Affiliation(s)
- Ming-Yao Wang
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Yi-Xuan Wang
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Jesse Li-Ling
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Hui-Qi Xie
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
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Shi S, Li F, Wu L, Zhang L, Liu L. Feasibility of Bone Marrow Mesenchymal Stem Cell-Mediated Synthetic Radiosensitive Promoter-Combined Sodium Iodide Symporter for Radiogenetic Ovarian Cancer Therapy. Hum Gene Ther 2021; 32:828-838. [PMID: 33339472 DOI: 10.1089/hum.2020.214] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Ovarian cancer is the most lethal gynecological cancer, most patients relapse within 12-24 months, and eventually die, especially platinum-resistant patients. Gene therapy has been one of the most potential methods for tumor treatment. Bone marrow mesenchymal stem cells (BMSCs) have been used for systemic delivery of therapeutic genes to solid tumors. Sodium iodide symporter (NIS) is an intrinsic membrane glycoprotein and can concentrate 131I, which is important for radionuclide therapy and nuclear medicine imaging in recent years. However, the rapid iodine efflux has become a bottleneck for NIS-mediated radionuclide gene therapy. Our previous studies found that the early growth response-1 (Egr1) promoter containing CC(A/T)6GG (CArG) elements had an 131I radiation-positive feedback effect on the NIS gene. Other research showed the synthesized Egr1 promoter containing four CArG elements, E4, was nearly three times as sensitive as the Egr1 promoter. In our study, BMSC-E4-NIS was engineered to express NIS under the control of E4 promoter using lentivirial vectors. After BMSC-E4-NIS implantation, no tumors were seen in BALB/c nude mice and BMSC-E4-NIS did not promote the growth of SKOV3 tumor. BMSCs migrated toward ovarian cancer samples in chemotaxis assays and to ovarian tumors in mice. Using micro-single-photon emission computed tomography/computed tomography (SPECT/CT) imaging, we found that E4 promoter produced a notable increase in 125I uptake after 131I irradiation, the radionuclide uptake is almost three and six times more than Egr1 and cytomegalovirus (CMV) promoters. These studies confirmed the feasibility of using BMSCs as carriers for lentivirus-mediated E4-NIS gene therapy for ovarian cancer. Further research on BMSC-E4-NIS gene therapy for ovarian cancer in vivo will also be carried on, and if successful, this might provide a new adjuvant therapeutical option for platinum-resistant ovarian cancer patients and provide a new method for dynamic evaluation of curative effect.
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Affiliation(s)
- Shuo Shi
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Fei Li
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Liangcai Wu
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Liwei Zhang
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Lei Liu
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
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Du Q, Ye X, Lu SR, Li H, Liu HY, Zhai Q, Yu B. Exosomal miR-30a and miR-222 derived from colon cancer mesenchymal stem cells promote the tumorigenicity of colon cancer through targeting MIA3. J Gastrointest Oncol 2021; 12:52-68. [PMID: 33708424 DOI: 10.21037/jgo-20-513] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background Multipotent mesenchymal stem cells (MSCs) derived from virus tumors have been reported to contribute to malignant cell growth, invasion, and metastasis. However, the mechanism of communication between MSCs and colon cancer cells is poorly understood. Recent studies have suggested that exosomes are an important player in crosstalk between cells and could significantly suppress the invasion ability of human cancer cells (hCCs) when transfected with a microRNA inhibitor. However, to date, no study has illuminated the miRNA changes in exosomes derived from hCC-MSCs. Methods Colon cancer stem cells were cultured in medium and passaged to develop fibroblast-like morphology. Exosomes were collected using ExoQuick precipitation and exosome morphology was visualized by transmission electron microscopy. Small RNA sequencing was analyzed using an Illumina HiSeq4000 analyzer, and the expression of MIA3 was assessed by real-time PCR and Western blot. The functional roles of miR-30a and miR-222 in colon cancer cells were evaluated through cell and animal experiments. Results Our results showed that the characteristics of MSC-like cells (hCC-MSCs) derived from human colon cancer stem cells were comparable to those of bone marrow-derived MSCs, including surface antigens and the ability to multi-differentiate to osteocytes and adipocytes. Furthermore, we screened the microRNA (miRNA) profiles of exosomes derived from hCC-MSCs and the corresponding parent hCC-MSCs. We found a significant enrichment in the miR-30a and miR-222 level in hCC-MSC-derived exosomes. Furthermore, in vitro and in vivo experiments demonstrated that miR-30a and miR-222 bound to their shared downstream target, MIA3, to promote the ability of colon cells to proliferate, migrate, and metastasize, thus evidencing their functional roles as oncogenic miRNAs. Conclusions These data suggest that hCC-MSC-secreted exosomes promote colon cancer cell proliferation and metastasis through delivering miR-30a and miR-222. Subsequently, exosomal miR-30a and miR-222 simultaneously target MIA3, suppress its expression, and promote colon cell proliferation, migration, and metastasis.
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Affiliation(s)
- Qiong Du
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xuan Ye
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Sheng-Rong Lu
- Department of Pharmacy, The Central Hospital of Min-Hang District, Shanghai, China
| | - Huan Li
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hong-Yue Liu
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qing Zhai
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Department of Pharmacy, The Central Hospital of Min-Hang District, Shanghai, China.,Department of Pharmacy, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bo Yu
- Department of Pharmacy, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Tarar A, Alyami EM, Peng CA. Mesenchymal stem cells anchored with thymidine phosphorylase for doxifluridine-mediated cancer therapy. RSC Adv 2021; 11:1394-1403. [PMID: 35424143 PMCID: PMC8693507 DOI: 10.1039/d0ra10263f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 12/23/2020] [Indexed: 12/11/2022] Open
Abstract
Many tumors express thymidine phosphorylase (TYMP) with various levels, however due to tumor heterogeneity, the amount of TYMP is usually not enough to convert prodrug doxifluridine (5'-DFUR) to toxic drug 5-fluorouracil (5-FU). Since human mesenchymal stem cells (hMSCs) have unique features of tumor-tropism and low immunogenicity, the purpose of this study is to use mesenchymal stem cells as carriers to deliver TYMP to cancer cells and then trigger their death by administrating doxifluridine. First, the TYMP gene sequence and core streptavidin (core SA) were constructed into pET-30a(+) plasmid. After bacterial transformation and colony screening, TYMP-SA fusion protein was expressed by IPTG induction and purified by immobilized metal affinity chromatography and characterized by SDS-PAGE and western blot with a clear band at 75 kDa. The characterized TYMP-SA was further anchored on the cell membrane of biotinylated hMSCs via biotin-streptavidin binding. hMSCs anchored with TYMP-SA were then co-cultured with adenocarcinoma A549 cells (with different ratios) and treated with 100 μM prodrug doxifluridine over the course of four days. Our results showed that a 2 : 1 ratio led to the eradication of A549 cells at the end of the experiment with less than 5% confluency, in comparison with the 1 : 1 and 1 : 2 ratios which still had about 13% and 20% confluency respectively. In conclusion, harnessing hMSCs as cell carriers for the delivery of TYMP enzyme to cancer cells could lead to significant cell death post-treatment of the prodrug doxifluridine.
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Affiliation(s)
- Ammar Tarar
- Department of Chemical & Biological Engineering, University of Idaho Engineering Physics Building 421, 875 Perimeter Drive Moscow ID 83844-0904 USA +1-208-885-7461
| | - Esmael M Alyami
- Department of Chemical & Biological Engineering, University of Idaho Engineering Physics Building 421, 875 Perimeter Drive Moscow ID 83844-0904 USA +1-208-885-7461
| | - Ching-An Peng
- Department of Chemical & Biological Engineering, University of Idaho Engineering Physics Building 421, 875 Perimeter Drive Moscow ID 83844-0904 USA +1-208-885-7461
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Sun Y, Tao Q, Wu X, Zhang L, Liu Q, Wang L. The Utility of Exosomes in Diagnosis and Therapy of Diabetes Mellitus and Associated Complications. Front Endocrinol (Lausanne) 2021; 12:756581. [PMID: 34764939 PMCID: PMC8576340 DOI: 10.3389/fendo.2021.756581] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 10/01/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus and the associated complications are metabolic diseases with high morbidity that result in poor quality of health and life. The lack of diagnostic methods for early detection results in patients losing the best treatment opportunity. Oral hypoglycemics and exogenous insulin replenishment are currently the most common therapeutic strategies, which only yield temporary glycemic control rather than curing the disease and its complications. Exosomes are nanoparticles containing bioactive molecules reflecting individual physiological status, regulating metabolism, and repairing damaged tissues. They function as biomarkers of diabetes mellitus and diabetic complications. Considering that exosomes are bioactive molecules, can be obtained from body fluid, and have cell-type specificity, in this review, we highlight the multifold effects of exosomes in the pathology and therapy of diabetes mellitus and diabetic complications.
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Affiliation(s)
- Yaoxiang Sun
- Department of Clinical Laboratory, Yixing People's Hospital, Yixing, China
| | - Qing Tao
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Xueqin Wu
- Department of Clinical Laboratory, Yixing People's Hospital, Yixing, China
| | - Ling Zhang
- Department of Clinical Laboratory, Yixing People's Hospital, Yixing, China
| | - Qi Liu
- Department of Clinical Laboratory, Yixing People's Hospital, Yixing, China
| | - Lei Wang
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
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Flavonoids Restore Platinum Drug Sensitivity to Ovarian Carcinoma Cells in a Phospho-ERK1/2-Dependent Fashion. Int J Mol Sci 2020; 21:ijms21186533. [PMID: 32906729 PMCID: PMC7555577 DOI: 10.3390/ijms21186533] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/23/2020] [Accepted: 09/02/2020] [Indexed: 12/15/2022] Open
Abstract
Ovarian cancer (OC) is the second most common type of gynecological malignancy; it has poor survival rates and is frequently (>75%) diagnosed at an advanced stage. Platinum-based chemotherapy, with, e.g., carboplatin, is the standard of care for OC, but toxicity and acquired resistance to therapy have proven challenging. Despite advances in OC diagnosis and treatment, approximately 85% of patients will experience relapse, mainly due to chemoresistance. The latter is attributed to alterations in the cancer cells and is also mediated by tumor microenvironment (TME). Recently, we reported the synthesis of a platinum (IV) prodrug that exhibits equal potency toward platinum-sensitive and resistant OC cell lines. Here, we investigated the effect of TME on platinum sensitivity. Co-culture of OC cells with murine or human mesenchymal stem cells (MS-5 and HS-5, respectively) rendered them resistant to chemotherapeutic agents, including platinum, paclitaxel and colchicine. Platinum resistance was also conferred by co-culture with differentiated murine adipocyte progenitor cells. Exposure of OC cells to chemotherapeutic agents resulted in activation of phospho-ERK1/2. Co-culture with MS-5, which conferred drug resistance, was accompanied by blockage of phospho-ERK1/2 activation. The flavonoids fisetin and quercetin were active in restoring ERK phosphorylation, as well as sensitivity to platinum compounds. Exposure of OC cells to cobimetinib-a MEK1 inhibitor that also inhibits extracellular signal-regulated kinase (ERK) phosphorylation-which resulted in reduced sensitivity to the platinum compound. This suggests that ERK activity is involved in mediating the function of flavonoids in restoring platinum sensitivity to OC co-cultured with cellular components of the TME. Our data show the potential of combining flavonoids with standard therapy to restore drug sensitivity to OC cells and overcome TME-mediated platinum drug resistance.
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Gonzalez-Villarreal CA, Quiroz-Reyes AG, Islas JF, Garza-Treviño EN. Colorectal Cancer Stem Cells in the Progression to Liver Metastasis. Front Oncol 2020; 10:1511. [PMID: 32974184 PMCID: PMC7468493 DOI: 10.3389/fonc.2020.01511] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 07/14/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal carcinoma (CRC) is a leading cause of cancer mortality. Tumorigenesis is a dynamic process wherein cancer stem cells (CSCs) and their microenvironment promote initiation, progression, and metastasis. Metastatic colonization is an inefficient process that is very complex and is poorly understood; however, in most cases, metastatic disease is not curable, and resistance mechanisms tend to develop against conventional treatments. An understanding of the underlying mechanisms and factors that contribute to the development of metastasis in CRC can aid in the search for specific therapeutic targets for improving standard treatments. In this review, we summarize current knowledge regarding tumor biology and the use of stroma cells as prognostic factors and inflammatory inducers associated with the use of tumor microenvironments as a promoter of cancer metastasis. Moreover, we look into the importance of CSC, pericytes, and circulating tumor cells as mechanisms that lead to liver metastasis, and we also focus on the cellular and molecular pathways that modulate and regulate epithelial–mesenchymal transition. Finally, we discuss a novel therapeutic target that can potentially eliminate CSCs as a CRC treatment.
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Affiliation(s)
| | - Adriana G Quiroz-Reyes
- Universidad Autonoma de Nuevo Leon Facultad de Medicina, Departamento de Bioquimica y Medicina Molecular, San Nicolás de los Garza, Mexico
| | - Jose F Islas
- Universidad Autonoma de Nuevo Leon Facultad de Medicina, Departamento de Bioquimica y Medicina Molecular, San Nicolás de los Garza, Mexico
| | - Elsa N Garza-Treviño
- Universidad Autonoma de Nuevo Leon Facultad de Medicina, Departamento de Bioquimica y Medicina Molecular, San Nicolás de los Garza, Mexico
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Reischl S, Wilhelm D, Friess H, Neumann PA. Innovative approaches for induction of gastrointestinal anastomotic healing: an update on experimental and clinical aspects. Langenbecks Arch Surg 2020; 406:971-980. [PMID: 32803330 PMCID: PMC8208906 DOI: 10.1007/s00423-020-01957-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 08/04/2020] [Indexed: 12/17/2022]
Abstract
PURPOSE In most cases, traditional techniques to perform an anastomosis following gastrointestinal resections lead to successful healing. However, despite focused research in the field, in certain high-risk situations leakage rates remain almost unchanged. Here, additional techniques may help the surgeon to protect the anastomosis and prevent leakage. We give an overview of some of the latest developments on experimental and clinical techniques for induction of anastomotic healing. METHODS We performed a review of the current literature on approaches to improve anastomotic healing. RESULTS Many promising approaches with a high clinical potential are in the developmental pipeline. Highly experimental approaches like inhibition of matrix metalloproteinases, stem cell therapy, hyperbaric oxygen therapy, induction of the hypoxic adaptive response, and the administration of growth factors are still in the preclinical phase. Other more clinical developments aim to strengthen the anastomotic suture line mechanically while shielding it from the influence of the microbiome. Among them are gluing, seaming the staple line, attachment of laminar biomaterials, and temporary intraluminal tubes. In addition, individualized bowel preparation, selectively reducing certain detrimental microbial populations could become the next stage of bowel preparation. Compression anastomoses are evolving as an equivalent technique additional to established hand-sewn and stapled anastomoses. Fluorescence angiography and flexible endoscopy could complement intraoperative quality control additionally to the air leak tests. Virtual ileostomy is a concept to prepare the bowel for the easy formation of a stoma in case of leakage. CONCLUSION A variety of promising diagnostic and prophylactic measures that may support the surgeon in identifying high-risk anastomoses and support them according to their potential deficits is currently in development.
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Affiliation(s)
- Stefan Reischl
- Department of Surgery, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Dirk Wilhelm
- Department of Surgery, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Helmut Friess
- Department of Surgery, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Philipp-Alexander Neumann
- Department of Surgery, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
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Role of MSC in the Tumor Microenvironment. Cancers (Basel) 2020; 12:cancers12082107. [PMID: 32751163 PMCID: PMC7464647 DOI: 10.3390/cancers12082107] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/24/2020] [Accepted: 07/25/2020] [Indexed: 12/24/2022] Open
Abstract
The tumor microenvironment represents a dynamically composed matrix in which tissue-associated cancer cells are embedded together with a variety of further cell types to form a more or less separate organ-like structure. Constantly mutual interactions between cells of the tumor microenvironment promote continuous restructuring and growth in the tumor. A distinct organization of the tumor stroma also facilitates the formation of transient cancer stem cell niches, thereby contributing to progressive and dynamic tumor development. An important but heterogeneous mixture of cells that communicates among the cancer cells and the different tumor-associated cell types is represented by mesenchymal stroma-/stem-like cells (MSC). Following recruitment to tumor sites, MSC can change their functionalities, adapt to the tumor's metabolism, undergo differentiation and synergize with cancer cells. Vice versa, cancer cells can alter therapeutic sensitivities and change metastatic behavior depending on the type and intensity of this MSC crosstalk. Thus, close cellular interactions between MSC and cancer cells can eventually promote cell fusion by forming new cancer hybrid cells. Consequently, newly acquired cancer cell functions or new hybrid cancer populations enlarge the plasticity of the tumor and counteract successful interventional strategies. The present review article highlights some important features of MSC within the tumor stroma.
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Costa LA, Eiro N, Fraile M, Gonzalez LO, Saá J, Garcia-Portabella P, Vega B, Schneider J, Vizoso FJ. Functional heterogeneity of mesenchymal stem cells from natural niches to culture conditions: implications for further clinical uses. Cell Mol Life Sci 2020; 78:447-467. [PMID: 32699947 PMCID: PMC7375036 DOI: 10.1007/s00018-020-03600-0] [Citation(s) in RCA: 190] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/02/2020] [Accepted: 07/13/2020] [Indexed: 12/11/2022]
Abstract
Mesenchymal stem cells (MSC) are present in all organs and tissues. Several studies have shown the therapeutic potential effect of MSC or their derived products. However, the functional heterogeneity of MSC constitutes an important barrier for transferring these capabilities to the clinic. MSC heterogeneity depends on their origin (biological niche) or the conditions of potential donors (age, diseases or unknown factors). It is accepted that many culture conditions of the artificial niche to which they are subjected, such as O2 tension, substrate and extracellular matrix cues, inflammatory stimuli or genetic manipulations can influence their resulting phenotype. Therefore, to attain a more personalized and precise medicine, a correct selection of MSC is mandatory, based on their functional potential, as well as the need to integrate all the existing information to achieve an optimal improvement of MSC features in the artificial niche.
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Affiliation(s)
- Luis A Costa
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33920, Gijón, Asturias, Spain
| | - Noemi Eiro
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33920, Gijón, Asturias, Spain
| | - María Fraile
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33920, Gijón, Asturias, Spain
| | - Luis O Gonzalez
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33920, Gijón, Asturias, Spain.,Department of Anatomical Pathology, Fundación Hospital de Jove, Gijón, Spain
| | - Jorge Saá
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33920, Gijón, Asturias, Spain
| | - Pablo Garcia-Portabella
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33920, Gijón, Asturias, Spain
| | - Belén Vega
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33920, Gijón, Asturias, Spain
| | - José Schneider
- Department of Obstetrics and Gynecology, University of Valladolid, Valladolid, Spain
| | - Francisco J Vizoso
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33920, Gijón, Asturias, Spain.
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Monteiro-Guerra F, Signorelli GR, Tadas S, Dorronzoro Zubiete E, Rivera Romero O, Fernandez-Luque L, Caulfield B. A Personalized Physical Activity Coaching App for Breast Cancer Survivors: Design Process and Early Prototype Testing. JMIR Mhealth Uhealth 2020; 8:e17552. [PMID: 32673271 PMCID: PMC7391671 DOI: 10.2196/17552] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 03/25/2020] [Accepted: 03/29/2020] [Indexed: 12/17/2022] Open
Abstract
Background Existing evidence supports the many benefits of physical activity (PA) in breast cancer survival. However, few breast cancer survivors adhere to the recommended levels of activity. A PA coaching app that provides personalized feedback, guidance, and motivation to the user might have the potential to engage these individuals in a more active lifestyle, in line with the general recommendations. To develop a successful tool, it is important to involve the end users in the design process and to make theoretically grounded design decisions. Objective This study aimed to execute the design process and early prototype evaluation of a personalized PA coaching app for posttreatment breast cancer survivors. In particular, the study explored a design combining behavioral theory and tailored coaching strategies. Methods The design process was led by a multidisciplinary team, including technical and health professionals, and involved input from a total of 22 survivors. The process comprised 3 stages. In stage 1, the literature was reviewed and 14 patients were interviewed to understand the needs and considerations of the target population toward PA apps. In stage 2, the global use case for the tool was defined, the features were ideated and refined based on theory, and a digital interactive prototype was created. In stage 3, the prototype went through usability testing with 8 patients and was subjected to quality and behavior change potential evaluations by 2 human-computer interaction experts. Results The design process has led to the conceptualization of a personalized coaching app for walking activities that addresses the needs of breast cancer survivors. The main features of the tool include a training plan and schedule, adaptive goal setting, real-time feedback and motivation during walking sessions, activity status through the day, activity history, weekly summary reports, and activity challenges. The system was designed to measure users’ cadence during walking, use this measure to infer their training zone, and provide real-time coaching to control the intensity of the walking sessions. The outcomes from user testing and expert evaluation of the digital prototype were very positive, with scores from the system usability scale, mobile app rating scale, and app behavior change scale of 95 out of 100, 4.6 out of 5, and 15 out of 21, respectively. Conclusions Implementing a user-centered design approach for the development and early evaluation of an app brings essential considerations to tailor the solution to the user’s needs and context. In addition, informing the design on behavioral and tailored coaching theories supports the conceptualization of the PA coaching system. This is critical for optimizing the usability, acceptability, and long-term effectiveness of the tool. After successful early in-laboratory testing, the app will be developed and evaluated in a pilot study in a real-world setting.
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Affiliation(s)
- Francisco Monteiro-Guerra
- Insight Centre for Data Analytics, School of Public Health, Physiotherapy and Sports Science, University College Dublin, Dublin, Ireland
| | - Gabriel Ruiz Signorelli
- Insight Centre for Data Analytics, School of Public Health, Physiotherapy and Sports Science, University College Dublin, Dublin, Ireland.,Salumedia Tecnologias, Seville, Spain
| | - Shreya Tadas
- Insight Centre for Data Analytics, School of Computer Science, University College Dublin, Dublin, Ireland
| | | | | | | | - Brian Caulfield
- Insight Centre for Data Analytics, School of Public Health, Physiotherapy and Sports Science, University College Dublin, Dublin, Ireland
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