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Li L, Yao Z, Salimian KJ, Kong J, Zaheer A, Parian A, Gearhart SL, Mao HQ, Selaru FM. Extracellular Vesicles Delivered by a Nanofiber-Hydrogel Composite Enhance Healing In Vivo in a Model of Crohn's Disease Perianal Fistula. Adv Healthc Mater 2025; 14:e2402292. [PMID: 39240055 PMCID: PMC11882933 DOI: 10.1002/adhm.202402292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Revised: 08/24/2024] [Indexed: 09/07/2024]
Abstract
Perianal fistulas represent a common, aggressive, and disabling complication of Crohn's disease (CD). Despite recent drug developments, novel surgical interventions as well as multidisciplinary treatment approaches, the outcome is dismal, with >50% therapy failure rates. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) offer potential therapeutic benefits for treating fistulizing CD, due to the pro-regenerative paracrine signals. However, a significant obstacle to clinical translation of EV-based therapy is the rapid clearance and short half-life of EVs in vivo. Here, an injectable, biodegradable nanofiber-hydrogel composite (NHC) microgel matrix that serves as a carrier to deliver MSC-derived EVs to a rat model of CD perianal fistula (PAF) is reported. It is found that EV-loaded NHC (EV-NHC) yields the best fistula healing when compared to other treatment arms. The MRI assessment reveals that the EV-NHC reduces inflammation at the fistula site and promotes tissue healing. The enhanced therapeutic outcomes are contributed by extended local retention and sustained release of EVs by NHC. In addition, the EV-NHC effectively reduces inflammation at the fistula site and promotes tissue healing and regeneration via macrophage polarization and neo-vascularization. This EV-NHC platform provides an off-the-shelf solution that facilitates its clinical translation.
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Affiliation(s)
- Ling Li
- Division of Gastroenterology and Hepatology, School of Medicine, Johns Hopkins University; Baltimore, Maryland, USA
| | - Zhicheng Yao
- Institute for NanoBioTechnology, Johns Hopkins University; Baltimore, Maryland, USA
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University; Baltimore, Maryland, USA
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine; Baltimore, Maryland, USA
| | - Kevan J. Salimian
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jiayuan Kong
- Institute for NanoBioTechnology, Johns Hopkins University; Baltimore, Maryland, USA
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University; Baltimore, Maryland, USA
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine; Baltimore, Maryland, USA
| | - Atif Zaheer
- Department of Radiology & Radiological Sciences, School of Medicine, Johns Hopkins University; Baltimore, Maryland, USA
| | - Alyssa Parian
- Division of Gastroenterology and Hepatology, School of Medicine, Johns Hopkins University; Baltimore, Maryland, USA
| | - Susan L. Gearhart
- Division of Colorectal Surgery, Department of Surgery, Johns Hopkins University School of Medicine; Baltimore, Maryland, USA
| | - Hai-Quan Mao
- Institute for NanoBioTechnology, Johns Hopkins University; Baltimore, Maryland, USA
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University; Baltimore, Maryland, USA
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine; Baltimore, Maryland, USA
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine; Baltimore, Maryland, USA
| | - Florin M. Selaru
- Division of Gastroenterology and Hepatology, School of Medicine, Johns Hopkins University; Baltimore, Maryland, USA
- Institute for NanoBioTechnology, Johns Hopkins University; Baltimore, Maryland, USA
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine; Baltimore, Maryland, USA
- Department of Oncology, Sidney Kimmel Cancer Center, School of Medicine, Johns Hopkins University; Baltimore, Maryland, USA
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Bader J, Brigger F, Leroux JC. Extracellular vesicles versus lipid nanoparticles for the delivery of nucleic acids. Adv Drug Deliv Rev 2024; 215:115461. [PMID: 39490384 DOI: 10.1016/j.addr.2024.115461] [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: 08/26/2024] [Revised: 10/21/2024] [Accepted: 10/23/2024] [Indexed: 11/05/2024]
Abstract
Extracellular vesicles (EVs) are increasingly investigated for delivering nucleic acid (NA) therapeutics, leveraging their natural role in transporting NA and protein-based cargo in cell-to-cell signaling. Their synthetic counterparts, lipid nanoparticles (LNPs), have been developed over the past decades as NA carriers, culminating in the approval of several marketed formulations such as patisiran/Onpattro® and the mRNA-1273/BNT162 COVID-19 vaccines. The success of LNPs has sparked efforts to develop innovative technologies to target extrahepatic organs, and to deliver novel therapeutic modalities, such as tools for in vivo gene editing. Fueled by the recent advancements in both fields, this review aims to provide a comprehensive overview of the basic characteristics of EV and LNP-based NA delivery systems, from EV biogenesis to structural properties of LNPs. It addresses the primary challenges encountered in utilizing these nanocarriers from a drug formulation and delivery perspective. Additionally, biodistribution profiles, in vitro and in vivo transfection outcomes, as well as their status in clinical trials are compared. Overall, this review provides insights into promising research avenues and potential dead ends for EV and LNP-based NA delivery systems.
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Affiliation(s)
- Johannes Bader
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Finn Brigger
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Jean-Christophe Leroux
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
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3
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Fagoonee S, Weiskirchen R. MicroRNAs and RNA-Binding Protein-Based Regulation of Bone Metastasis from Hepatobiliary Cancers and Potential Therapeutic Strategies. Cells 2024; 13:1935. [PMID: 39682684 PMCID: PMC11640337 DOI: 10.3390/cells13231935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 11/15/2024] [Accepted: 11/20/2024] [Indexed: 12/18/2024] Open
Abstract
Hepatobiliary cancers, such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are among the deadliest malignancies worldwide, leading to a significant number of cancer-related deaths. While bone metastases from these cancers are rare, they are highly aggressive and linked to poor prognosis. This review focuses on RNA-based molecular mechanisms that contribute to bone metastasis from hepatobiliary cancers. Specifically, the role of two key factors, microRNAs (miRNAs) and RNA-binding proteins (RBPs), which have not been extensively studied in the context of HCC and CCA, is discussed. These molecules often exhibit abnormal expression in hepatobiliary tumors, influencing cancer cell spread and metastasis by disrupting bone homeostasis, thereby aiding tumor cell migration and survival in the bone microenvironment. This review also discusses potential therapeutic strategies targeting these RNA-based pathways to reduce bone metastasis and improve patient outcomes. Further research is crucial for developing effective miRNA- and RBP-based diagnostic and prognostic biomarkers and treatments to prevent bone metastases in hepatobiliary cancers.
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Affiliation(s)
- Sharmila Fagoonee
- Institute of Biostructure and Bioimaging (CNR), Molecular Biotechnology Center “Guido Tarone”, 10126 Turin, Italy
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany
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Fu H, Dong S, Li K. Identification of SLC31A1 as a prognostic biomarker and a target for therapeutics in breast cancer. Sci Rep 2024; 14:25120. [PMID: 39448672 PMCID: PMC11502855 DOI: 10.1038/s41598-024-76162-x] [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: 05/15/2023] [Accepted: 10/10/2024] [Indexed: 10/26/2024] Open
Abstract
Copper-induced cell death is regulated through protein lipoylation, which is critical for gene expression and phenotypic regulation. Neverless, the role of Cuproptosis-related genes in breast cancer (BC) remains unknown. This study aimed to construct a prognostic signature based on the expression of Cuproptosis-related genes in order to guide the diagnosis and treatment for BC. Cuproptosis-related genes prognostic signature has ata of 1250 BC tissues and 583 normal breast tissues were obtained from The Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx), and GEO GSE65212. The prognostic signature was established and evaluated with nineteen Cuproptosis-related genes. A series of in silico analyses based on SLC31A1, included expression analysis, independent prognostic analysis, correlation analysis, immune-related analysis and survival analysis. Finally, a series of cell experiments (including quantitative real-time polymerase chain reaction and western blot), and mice experiments were applied to evaluate the impact of SLC31A1 on BC. Cuproptosis-related genes prognostic signature has good predictive promising for survival in BC patients. We discovered that SLC31A1SLC31A1 was overexpressed in BC and was its independent prognostic factor. High expression of the SLC31A1 was correlated with poor prognosis and immune infiltrating of BC. SLC31A1 expression is associated with immune, chemotherapeutic and targeted therapy outcomes in BC. The proliferation, migration, and invasiveness of Her2 + enriched BC cells were decreased by SLC31A1 knockdown, also resulting in a decrease in tumor volume in mouse model. SLC31A1 is a candidate biomarker or therapeutic target in precision oncology, with diagnostic and prognostic significance in BC.
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Affiliation(s)
- Hongtao Fu
- Department of Breast Surgery, Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410006, Hunan, China
- Department of Breast Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210000, China
| | - Shanshan Dong
- Department of Medicine, Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, China
| | - Kun Li
- Department of Emergency Medicine, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, 161 Shaoshan South Road, Changsha, 410000, China.
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Wang Q, Sun X, Fang X, Wang Z, Wang H, Sun S, Wang S, Li T, Zhang P, Cheng Z. Dual-molecular targeting nanomedicine upregulates synergistic therapeutic efficacy in preclinical hepatoma models. Acta Biomater 2024; 183:306-317. [PMID: 38838902 DOI: 10.1016/j.actbio.2024.05.045] [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: 04/07/2024] [Revised: 05/11/2024] [Accepted: 05/30/2024] [Indexed: 06/07/2024]
Abstract
Advanced hepatocellular carcinoma (HCC) is one of the most challenging cancers because of its heterogeneous and aggressive nature, precluding the use of curative treatments. Sorafenib (SOR) is the first approved molecular targeting agent against the mitogen-activated protein kinase (MAPK) pathway for the noncurative therapy of advanced HCC; yet, any clinically meaningful benefits from the treatment remain modest, and are accompanied by significant side effects. Here, we hypothesized that using a nanomedicine platform to co-deliver SOR with another molecular targeting drug, metformin (MET), could tackle these issues. A micelle self-assembled with amphiphilic polypeptide methoxy poly(ethylene glycol)-block-poly(L-phenylalanine-co-l-glutamic acid) (mPEG-b-P(LP-co-LG)) (PM) was therefore designed for combinational delivery of two molecular targeted drugs, SOR and MET, to hepatomas. Compared with free drugs, the proposed, dual drug-loaded micelle (PM/SOR+MET) enhanced the drugs' half-life in the bloodstream and drug accumulation at the tumor site, thereby inhibiting tumor growth effectively in the preclinical subcutaneous, orthotopic and patient-derived xenograft hepatoma models without causing significant systemic and organ toxicity. Collectively, these findings demonstrate an effective dual-targeting nanomedicine strategy for treating advanced HCC, which may have a translational potential for cancer therapeutics. STATEMENT OF SIGNIFICANCE: Treatment of advanced hepatocellular carcinoma (HCC) remains a formidable challenge due to its aggressive nature and the limitations inherent to current therapies. Despite advancements in molecular targeted therapies, such as Sorafenib (SOR), their modest clinical benefits coupled with significant adverse effects underscore the urgent need for more efficacious and less toxic treatment modalities. Our research presents a new nanomedicine platform that synergistically combines SOR with metformin within a specialized diblock polypeptide micelle, aiming to enhance therapeutic efficacy while reducing systemic toxicity. This innovative approach not only exhibits marked antitumor efficacy across multiple HCC models but also significantly reduces the toxicity associated with current treatments. Our dual-molecular targeting approach unveils a promising nanomedicine strategy for the molecular treatment of advanced HCC, potentially offering more effective and safer treatment alternatives with significant translational potential.
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Affiliation(s)
- Qilong Wang
- Department of Vascular Surgery, General Surgery Center, the First Hospital of Jilin University, Changchun, 130061, PR China
| | - Xiwei Sun
- Department of Vascular Surgery, General Surgery Center, the First Hospital of Jilin University, Changchun, 130061, PR China
| | - Xizhu Fang
- Department of Immunology and Pathogenic Biology, College of Medicine, Yanbian University, Yanji, 133002, PR China
| | - Zhongying Wang
- Department of Vascular Surgery, General Surgery Center, the First Hospital of Jilin University, Changchun, 130061, PR China
| | - Haodong Wang
- Department of Vascular Surgery, General Surgery Center, the First Hospital of Jilin University, Changchun, 130061, PR China
| | - Siqiao Sun
- Department of Vascular Surgery, General Surgery Center, the First Hospital of Jilin University, Changchun, 130061, PR China
| | - Shuai Wang
- Department of Vascular Surgery, General Surgery Center, the First Hospital of Jilin University, Changchun, 130061, PR China
| | - Tingting Li
- Department of Vascular Surgery, General Surgery Center, the First Hospital of Jilin University, Changchun, 130061, PR China
| | - Ping Zhang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, the First Hospital of Jilin University, Changchun, 130061, PR China.
| | - Zhihua Cheng
- Department of Vascular Surgery, General Surgery Center, the First Hospital of Jilin University, Changchun, 130061, PR China.
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Sheng Z, Wang X, Ding X, Zheng Y, Guo A, Cui J, Ma J, Duan W, Dong H, Zhang H, Cui M, Su W, Zhang B. Exosomal miRNA-92a derived from cancer-associated fibroblasts promote invasion and metastasis in breast cancer by regulating G3BP2. Cell Signal 2024; 119:111182. [PMID: 38640983 DOI: 10.1016/j.cellsig.2024.111182] [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: 01/23/2024] [Revised: 04/07/2024] [Accepted: 04/16/2024] [Indexed: 04/21/2024]
Abstract
Cancer-associated Fibroblasts (CAFs) exert a tumor-promoting effect in various cancers, including breast cancer. CAFs secrete exosomes containing miRNA and proteins, influencing the tumor microenvironment. In this study, we identified CAF-derived exosomes that transport functional miR-92a from CAFs to tumor cells, thereby intensifying the aggressiveness of breast cancer. CAFs downregulate the expression of G3BP2 in breast cancer cells, and a significant elevation in miR-92a levels in CAF-derived exosomes was observed. Both in vitro and in vivo experiments demonstrate that miR-92a enhances breast cancer cell migration and invasion by directly targeting G3BP2, functioning as a tumor-promoting miRNA. We validated that the RNA-binding proteins SNRPA facilitate the transfer of CAF-derived exosomal miR-92a to breast cancer cells. The reduction of G3BP2 protein by CAF-derived exosomes releases TWIST1 into the nucleus, promoting epithelial-mesenchymal transition (EMT) and further exacerbating breast cancer progression. Moreover, CAF-derived exosomal miR-92a induces tumor invasion and metastasis in mice. Overall, our study reveals that CAF-derived exosomal miR-92a serves as a promoter in the migration and invasion of breast cancer cells by reducing G3BP2 and may represent a potential novel tumor marker for breast cancer.
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Affiliation(s)
- Zhimei Sheng
- Department of Pathology, School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong, China; Department of Pathology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Xuejie Wang
- Department of Pathology, School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong, China
| | - Xiaodi Ding
- Department of Pathology, School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong, China
| | - Yuanhang Zheng
- Department of Pathology, Weifang people's Hospital, Weifang, Shandong, China
| | - Ai Guo
- Department of Pathology, School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong, China
| | - Jiayu Cui
- Department of Pathology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Jing Ma
- Department of Pathology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Wanli Duan
- Department of Pathology, School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong, China
| | - Hao Dong
- Department of Pathology, School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong, China
| | - Hongxing Zhang
- Department of Pathology, School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong, China
| | - Meimei Cui
- Department of Pathology, School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong, China
| | - Wenxia Su
- Department of Physiology, Second Medical University, Weifang, Shandong, China
| | - Baogang Zhang
- Department of Pathology, School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong, China; Department of Pathology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China.
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Guo X, Wang J, Tian Y, Yang J, Wu S, Xin L, Feng Z, Niu G. Epigenetic silencing of miR-125a-3p promotes the progress of human cholangiocarcinoma via increasing CAC1 expression. Heliyon 2024; 10:e32528. [PMID: 38994075 PMCID: PMC11237926 DOI: 10.1016/j.heliyon.2024.e32528] [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: 01/21/2024] [Revised: 06/04/2024] [Accepted: 06/05/2024] [Indexed: 07/13/2024] Open
Abstract
We aimed to investigate the dysregulation of the microRNAs(miRNAs) in cholangiocarcinoma (CCA), including its impact on the homeostasis of the transcriptome and cellular behavior. MiRNAs serve as potent epigenetic regulators of transcriptional output, targeting various signaling pathways. This study aimed to investigate the expression level, epigenetic mechanism and function of miR-125a-3 in CCA. The study data showed that the expression level of miR125a-3p was decreased in CCA tissue samples and cell lines, and it was closely related to lymph node metastasis, tissue differentiation and TNM stage. The data demonstrate a strong association between decreased miR-125a-3p expression and poorer prognosis in cholangiocarcinoma patients. miR-125a-3p acts as a tumor suppressor by inhibiting the viability, migration and invasion of CCA cells. There are CpG islands in the promoter region of miR-125a-3p gene, and the methylation of the promoter region of miR-125a-3p gene leads to the transcriptional repression of miR-125a-3p. In addition, miR125a-3p can target and regulate CAC1 mRNA and protein expression in the downstream mechanism, and the high expression of CAC1 can promote the proliferation, migration and invasion of cholangiocarcinoma cells. These data demonstrate that miR-125a-3p promoter methylation leads to silencing of its expression. Mechanically, miR-125a-3p acts as a tumor suppressor and participates in the occurrence and development of CCA through targeting CAC1 gene expression. Therefore, miR-125a-3p may serve as a new target for the diagnosis, prognostic assessment or molecular therapy of CCA.
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Affiliation(s)
- Xiaojuan Guo
- Department of Pathology, Handan Center Hospital, Handan, 056002, China
| | - Jinxi Wang
- The Fourth Department of General Surgery, The First Hospital of Handan, Handan, 056002, China
| | - Yunxiao Tian
- Department of Pathology, Handan Center Hospital, Handan, 056002, China
| | - Jianhua Yang
- Department of Pathology, Handan Center Hospital, Handan, 056002, China
| | - Shiqian Wu
- Department of Pathology, Handan Center Hospital, Handan, 056002, China
| | - Lihui Xin
- Department of Pathology, Handan Center Hospital, Handan, 056002, China
| | - Zhe Feng
- Department of Function, Handan Center Hospital, Handan, 056002, China
| | - Guangxu Niu
- Department of Pathology, Handan Center Hospital, Handan, 056002, China
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Jiang S, Tian S, Wang P, Liu J, Sun K, Zhou X, Han Y, Shang Y. Native and engineered extracellular vesicles: novel tools for treating liver disease. J Mater Chem B 2024; 12:3840-3856. [PMID: 38532706 DOI: 10.1039/d3tb01921g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/28/2024]
Abstract
Liver diseases are classified as acute liver damage and chronic liver disease, with recurring liver damage causing liver fibrosis and progression to cirrhosis and hepatoma. Liver transplantation is the only effective treatment for end-stage liver diseases; therefore, novel therapies are required. Extracellular vesicles (EVs) are endogenous nanocarriers involved in cell-to-cell communication that play important roles in immune regulation, tissue repair and regeneration. Native EVs can potentially be used for various liver diseases owing to their high biocompatibility, low immunogenicity and tissue permeability and engineered EVs with surface modification or cargo loading could further optimize therapeutic effects. In this review, we firstly introduced the mechanisms and effects of native EVs derived from different cells and tissues to treat liver diseases of different etiologies. Additionally, we summarized the possible methods to facilitate liver targeting and improve cargo-loading efficiency. In the treatment of liver disease, the detailed engineered methods and the latest delivery strategies were also discussed. Finally, we pointed out the limitations and challenges of EVs for future development and applications. We hope that this review could provide a useful reference for the development of EVs and promote the clinical translation.
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Affiliation(s)
- Shuangshuang Jiang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Siyuan Tian
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Punan Wang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Jingyi Liu
- Department of Radiation Oncology, Xijing Hospital, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Keshuai Sun
- Department of Gastroenterology, The Air Force Hospital From Eastern Theater of PLA, Nanjing, 210002, Jiangsu, China
| | - Xia Zhou
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Ying Han
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Yulong Shang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.
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9
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Gou Z, Li J, Liu J, Yang N. The hidden messengers: cancer associated fibroblasts-derived exosomal miRNAs as key regulators of cancer malignancy. Front Cell Dev Biol 2024; 12:1378302. [PMID: 38694824 PMCID: PMC11061421 DOI: 10.3389/fcell.2024.1378302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 04/08/2024] [Indexed: 05/04/2024] Open
Abstract
Cancer-associated fibroblasts (CAFs), a class of stromal cells in the tumor microenvironment (TME), play a key role in controlling cancer cell invasion and metastasis, immune evasion, angiogenesis, and resistance to chemotherapy. CAFs mediate their activities by secreting soluble chemicals, releasing exosomes, and altering the extracellular matrix (ECM). Exosomes contain various biomolecules, such as nucleic acids, lipids, and proteins. microRNA (miRNA), a 22-26 nucleotide non-coding RNA, can regulate the cellular transcription processes. Studies have shown that miRNA-loaded exosomes secreted by CAFs engage in various regulatory communication networks with other TME constituents. This study focused on the roles of CAF-derived exosomal miRNAs in generating cancer malignant characteristics, including immune modulation, tumor growth, migration and invasion, epithelial-mesenchymal transition (EMT), and treatment resistance. This study thoroughly examines miRNA's dual regulatory roles in promoting and suppressing cancer. Thus, changes in the CAF-derived exosomal miRNAs can be used as biomarkers for the diagnosis and prognosis of patients, and their specificity can be used to develop newer therapies. This review also discusses the pressing problems that require immediate attention, aiming to inspire researchers to explore more novel avenues in this field.
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Affiliation(s)
- Zixuan Gou
- Bethune First Clinical School of Medicine, The First Hospital of Jilin University, Changchun, China
| | - Jiannan Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Jianming Liu
- Department of Otolaryngology Head and Neck Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Na Yang
- Department of Clinical Pharmacy, The First Hospital of Jilin University, Changchun, China
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Wang J, Shi R, Yin Y, Luo H, Cao Y, Lyu Y, Luo H, Zeng X, Wang D. Clinical significance of small extracellular vesicles in cholangiocarcinoma. Front Oncol 2024; 14:1334592. [PMID: 38665948 PMCID: PMC11043544 DOI: 10.3389/fonc.2024.1334592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 03/28/2024] [Indexed: 04/28/2024] Open
Abstract
Cholangiocarcinoma is an aggressive and heterogeneous malignancy originating from the bile duct epithelium. It is associated with poor prognosis and high mortality. The global incidence of cholangiocarcinoma is rising, and there is an urgent need for effective early diagnosis and treatment strategies to reduce the burden of this devastating tumor. Small extracellular vesicles, including exosomes and microparticles, are nanoscale vesicles formed by membranes that are released both normally and pathologically from cells, mediating the intercellular transfer of substances and information. Recent studies have demonstrated the involvement of small extracellular vesicles in numerous biological processes, as well as the proliferation, invasion, and metastasis of tumor cells. The present review summarizes the tumorigenic roles of small extracellular vesicles in the cholangiocarcinoma microenvironment. Owing to their unique composition, accessibility, and stability in biological fluids, small extracellular vesicles have emerged as ideal biomarkers for use in liquid biopsies for diagnosing and outcome prediction of cholangiocarcinoma. Specific tissue tropism, theoretical biocompatibility, low clearance, and strong biological barrier penetration of small extracellular vesicles make them suitable drug carriers for cancer therapy. Furthermore, the potential value of small extracellular vesicle-based therapies for cholangiocarcinoma is also reviewed.
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Affiliation(s)
- Jianjun Wang
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Ruizi Shi
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Yuan Yin
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Hua Luo
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Yuan Cao
- Department of Urology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Yun Lyu
- Departmant of Oncology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Huiwen Luo
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Xintao Zeng
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Decai Wang
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
- Department of Urology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
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11
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Cantallops Vilà P, Ravichandra A, Agirre Lizaso A, Perugorria MJ, Affò S. Heterogeneity, crosstalk, and targeting of cancer-associated fibroblasts in cholangiocarcinoma. Hepatology 2024; 79:941-958. [PMID: 37018128 DOI: 10.1097/hep.0000000000000206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 11/25/2022] [Indexed: 04/06/2023]
Abstract
Cholangiocarcinoma (CCA) comprises diverse tumors of the biliary tree and is characterized by late diagnosis, short-term survival, and chemoresistance. CCAs are mainly classified according to their anatomical location and include diverse molecular subclasses harboring inter-tumoral and intratumoral heterogeneity. Besides the tumor cell component, CCA is also characterized by a complex and dynamic tumor microenvironment where tumor cells and stromal cells crosstalk in an intricate network of interactions. Cancer-associated fibroblasts, one of the most abundant cell types in the tumor stroma of CCA, are actively involved in cholangiocarcinogenesis by participating in multiple aspects of the disease including extracellular matrix remodeling, immunomodulation, neo-angiogenesis, and metastasis. Despite their overall tumor-promoting role, recent evidence indicates the presence of transcriptional and functional heterogeneous CAF subtypes with tumor-promoting and tumor-restricting properties. To elucidate the complexity and potentials of cancer-associated fibroblasts as therapeutic targets in CCA, this review will discuss the origin of cancer-associated fibroblasts, their heterogeneity, crosstalk, and role during tumorigenesis, providing an overall picture of the present and future perspectives toward cancer-associated fibroblasts targeting CCA.
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Affiliation(s)
| | - Aashreya Ravichandra
- Medical Clinic and Polyclinic II, Klinikum Rechts Der Isar, Technical University Munich, Munich, Germany
| | - Aloña Agirre Lizaso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain
- CIBERehd, Institute of Health Carlos III, Madrid, Spain
- Department of Medicine, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Leioa, Spain
| | - Silvia Affò
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
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12
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Guo C, Sachithanandham J, Zhong W, Craney M, Villano J, Pekosz A, Gould SJ. Antigen-display exosomes provide adjuvant-free protection against SARS-CoV-2 disease at nanogram levels of spike protein. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.04.574272. [PMID: 38328234 PMCID: PMC10849639 DOI: 10.1101/2024.01.04.574272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
As the only bionormal nanovesicle, exosomes have high potential as a nanovesicle for delivering vaccines and therapeutics. We show here that the loading of type-1 membrane proteins into the exosome membrane is induced by exosome membrane anchor domains, EMADs, that maximize protein delivery to the plasma membrane, minimize protein sorting to other compartments, and direct proteins into exosome membranes. Using SARS-CoV-2 spike as an example and EMAD13 as our most effective exosome membrane anchor, we show that cells expressing a spike-EMAD13 fusion protein produced exosomes that carry dense arrays of spike trimers on 50% of all exosomes. Moreover, we find that immunization with spike-EMAD13 exosomes induced strong neutralizing antibody responses and protected hamsters against SARS-CoV-2 disease at doses of just 0.5-5 ng of spike protein, without adjuvant, demonstrating that antigen-display exosomes are particularly immunogenic, with important implications for both structural and expression-dependent vaccines.
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Affiliation(s)
- Chenxu Guo
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Jaiprasath Sachithanandham
- Department of Microbiology and Immunology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205
| | - William Zhong
- Department of Microbiology and Immunology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205
| | - Morgan Craney
- Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Jason Villano
- Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Andrew Pekosz
- Department of Microbiology and Immunology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205
| | - Stephen J Gould
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
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13
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Zhou X, Zhang B, Hu J, Shen J, Chen Z, Zhang J, Wu B, Zhou E, Peng S, Wong TW, Yang G, Cao J, Chen M. Igniting cold tumors of intrahepatic cholangiocarcinoma: An insight into immune evasion and tumor immune microenvironment. THE INNOVATION MEDICINE 2024; 2:100052. [DOI: 10.59717/j.xinn-med.2024.100052] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
<p>Intrahepatic cholangiocarcinoma (ICC) is a rare hepatobiliary cancer that originates from the epithelium of the intrahepatic bile duct. The various treatments for ICC, such as chemotherapy, radiotherapy, and locoregional therapy, confer only modest improvements in survival rates. Immunotherapy, although revolutionary in cancer treatment, has found limited application in the treatment of ICCs due to the “cold” nature of these tumors, which is marked by scant T-cell infiltration. This characteristic makes immune checkpoint inhibitors (ICIs) unsuitable for the majority of ICC patients. Therefore, comprehensively understanding the mechanisms underlying these “cold” tumors is crucial for harnessing the potential of immunotherapy for treating ICC patients. This paper explores immune evasion mechanisms and the complex tumor immune microenvironment of ICC. This study provides a comprehensive overview of therapeutic strategies aimed at activating cold tumors and enhancing their immunogenicity. Furthermore, potential and promising targets for cancer vaccines and adoptive cellular therapy in the context of ICC are discussed. This endeavor strives to reveal new pathways for innovative immunotherapy strategies, with a focus on overcoming the key challenge of triggering an effective immune response in ICC patients.</p>
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14
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Zhang Y, Yan HJ, Wu J. The Tumor Immune Microenvironment plays a Key Role in Driving the Progression of Cholangiocarcinoma. Curr Cancer Drug Targets 2024; 24:681-700. [PMID: 38213139 DOI: 10.2174/0115680096267791231115101107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 10/09/2023] [Accepted: 10/13/2023] [Indexed: 01/13/2024]
Abstract
Cholangiocarcinoma (CCA) is an epithelial cancer distinguished by bile duct cell differentiation and is also a fibroproliferative tumor. It is characterized by a dense mesenchyme and a complex tumor immune microenvironment (TME). The TME comprises both cellular and non-cellular components. The celluar component includes CCA cells, immune cells and mesenchymal cells represented by the cancer-associated fibroblasts (CAFs), while the non-cellular component is represented by mesenchymal elements such as the extracellular matrix (ECM). Recent studies have demonstrated the important role of the TME in the development, progression, and treatment resistance of CCA. These cell-associated prognostic markers as well as intercellular connections, may serve as potential therapeutic targets and could inspire new treatment approaches for CCA in the future. This paper aims to summarize the current understanding of CCA's immune microenvironment, focusing on immune cells, mesenchymal cells, ECM, intercellular interactions, and metabolism within the microenvironment.
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Affiliation(s)
- Ye Zhang
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian St, Changzhou, 213003, China
| | - Hai-Jiao Yan
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian St, Changzhou, 213003, China
| | - Jun Wu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian St, Changzhou, 213003, China
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15
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Trifylli EM, Kriebardis AG, Koustas E, Papadopoulos N, Vasileiadi S, Fortis SP, Tzounakas VL, Anastasiadi AT, Sarantis P, Papageorgiou EG, Tsagarakis A, Aloizos G, Manolakopoulos S, Deutsch M. The Arising Role of Extracellular Vesicles in Cholangiocarcinoma: A Rundown of the Current Knowledge Regarding Diagnostic and Therapeutic Approaches. Int J Mol Sci 2023; 24:15563. [PMID: 37958547 PMCID: PMC10649642 DOI: 10.3390/ijms242115563] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 10/21/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Cholangiocarcinomas (CCAs) constitute a heterogeneous group of highly malignant epithelial tumors arising from the biliary tree. This cluster of malignant tumors includes three distinct entities, the intrahepatic, perihilar, and distal CCAs, which are characterized by different epidemiological and molecular backgrounds, as well as prognosis and therapeutic approaches. The higher incidence of CCA over the last decades, the late diagnostic time that contributes to a high mortality and poor prognosis, as well as its chemoresistance, intensified the efforts of the scientific community for the development of novel diagnostic tools and therapeutic approaches. Extracellular vesicles (EVs) comprise highly heterogenic, multi-sized, membrane-enclosed nanostructures that are secreted by a large variety of cells via different routes of biogenesis. Their role in intercellular communication via their cargo that potentially contributes to disease development and progression, as well as their prospect as diagnostic biomarkers and therapeutic tools, has become the focus of interest of several current studies for several diseases, including CCA. The aim of this review is to give a rundown of the current knowledge regarding the emerging role of EVs in cholangiocarcinogenesis and their future perspectives as diagnostic and therapeutic tools.
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Affiliation(s)
- Eleni-Myrto Trifylli
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, Section of Medical Laboratories, School of Health & Caring Sciences, University of West Attica (UniWA), Ag. Spyridonos Str., 12243 Egaleo, Greece; (E.-M.T.); (S.P.F.); (E.G.P.)
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece;
- 2nd Academic Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Hippokration General Hospital of Athens, Vasilissis Sofias Avenue Str., 11527 Athens, Greece; (S.V.); (S.M.); (M.D.)
| | - Anastasios G. Kriebardis
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, Section of Medical Laboratories, School of Health & Caring Sciences, University of West Attica (UniWA), Ag. Spyridonos Str., 12243 Egaleo, Greece; (E.-M.T.); (S.P.F.); (E.G.P.)
| | - Evangelos Koustas
- Oncology Department, General Hospital Evangelismos, 10676 Athens, Greece;
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Nikolaos Papadopoulos
- Second Department of Internal Medicine, 401 General Military Hospital, 115 27 Athens, Greece;
| | - Sofia Vasileiadi
- 2nd Academic Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Hippokration General Hospital of Athens, Vasilissis Sofias Avenue Str., 11527 Athens, Greece; (S.V.); (S.M.); (M.D.)
| | - Sotirios P. Fortis
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, Section of Medical Laboratories, School of Health & Caring Sciences, University of West Attica (UniWA), Ag. Spyridonos Str., 12243 Egaleo, Greece; (E.-M.T.); (S.P.F.); (E.G.P.)
| | - Vassilis L. Tzounakas
- Department of Biochemistry, School of Medicine, University of Patras, 26504 Patras, Greece; (V.L.T.); (A.T.A.)
| | - Alkmini T. Anastasiadi
- Department of Biochemistry, School of Medicine, University of Patras, 26504 Patras, Greece; (V.L.T.); (A.T.A.)
| | - Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Effie G. Papageorgiou
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, Section of Medical Laboratories, School of Health & Caring Sciences, University of West Attica (UniWA), Ag. Spyridonos Str., 12243 Egaleo, Greece; (E.-M.T.); (S.P.F.); (E.G.P.)
| | - Ariadne Tsagarakis
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA;
| | - Georgios Aloizos
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece;
| | - Spilios Manolakopoulos
- 2nd Academic Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Hippokration General Hospital of Athens, Vasilissis Sofias Avenue Str., 11527 Athens, Greece; (S.V.); (S.M.); (M.D.)
| | - Melanie Deutsch
- 2nd Academic Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Hippokration General Hospital of Athens, Vasilissis Sofias Avenue Str., 11527 Athens, Greece; (S.V.); (S.M.); (M.D.)
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16
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Liu M, Lai Z, Yuan X, Jin Q, Shen H, Rao D, Huang D. Role of exosomes in the development, diagnosis, prognosis and treatment of hepatocellular carcinoma. Mol Med 2023; 29:136. [PMID: 37848835 PMCID: PMC10580543 DOI: 10.1186/s10020-023-00731-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 09/17/2023] [Indexed: 10/19/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer. It is characterized by occult onset resulting in most patients being diagnosed at advanced stages and with poor prognosis. Exosomes are nanoscale vesicles with a lipid bilayer envelope released by various cells under physiological and pathological conditions, which play an important role in the biological information transfer between cells. There is growing evidence that HCC cell-derived exosomes may contribute to the establishment of a favorable microenvironment that supports cancer cell proliferation, invasion, and metastasis. These exosomes not only provide a versatile platform for diagnosis but also serve as a vehicle for drug delivery. In this paper, we review the role of exosomes involved in the proliferation, migration, and metastasis of HCC and describe their application in HCC diagnosis and treatment. We also discuss the prospects of exosome application in HCC and the research challenges.
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Affiliation(s)
- Meijin Liu
- Ganzhou Jingkai District People's Hospital, Ganzhou, China
| | - Zhonghong Lai
- Department of Traumatology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Xiaoying Yuan
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Qing Jin
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Haibin Shen
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Dingyu Rao
- Department of Cardiothoracic Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
| | - Defa Huang
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
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17
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Davoodvandi A, Rafiyan M, Asemi Z, Matini SA. An epigenetic modulator with promising therapeutic impacts against gastrointestinal cancers: A mechanistic review on microRNA-195. Pathol Res Pract 2023; 248:154680. [PMID: 37467635 DOI: 10.1016/j.prp.2023.154680] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/06/2023] [Accepted: 07/07/2023] [Indexed: 07/21/2023]
Abstract
Due to their high prevalence, gastrointestinal cancers are one of the key causes of cancer-related death globally. The development of drug-resistant cancer cell populations is a major factor in the high mortality rate, and it affects about half of all cancer patients. Because of advances in our understanding of cancer molecular biology, non-coding RNAs (ncRNAs) have emerged as critical factors in the initiation and development of gastrointestinal cancers. Gene expression can be controlled in several ways by ncRNAs, including through epigenetic changes, interactions between microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) and proteins, and the function of lncRNAs as miRNA precursors or pseudogenes. As lncRNAs may be detected in the blood, circulating ncRNAs have emerged as a promising new class of non-invasive cancer biomarkers for use in the detection, staging, and prognosis of gastrointestinal cancers, as well as in the prediction of therapy efficacy. In this review, we assessed the role lncRNAs play in the progression, and maintenance of colorectal cancer, and how they might be used as therapeutic targets in the future.
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Affiliation(s)
- Amirhossein Davoodvandi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, I.R. Iran.
| | - Mahdi Rafiyan
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, I.R. Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, I.R. Iran.
| | - Seyed Amirhassan Matini
- Department of Pathology, School of Medicine, Kashan University of Medical Sciences, Kashan, I.R. Iran.
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18
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Huang Y, Zhu X, Guo X, Zhou Y, Liu D, Mao J, Xiong Y, Deng Y, Gao X. Advances in mRNA vaccines for viral diseases. J Med Virol 2023; 95:e28924. [PMID: 37417396 DOI: 10.1002/jmv.28924] [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: 02/21/2023] [Revised: 05/25/2023] [Accepted: 06/20/2023] [Indexed: 07/08/2023]
Abstract
Since the onset of the pandemic caused by severe acute respiratory syndrome coronavirus 2, messenger RNA (mRNA) vaccines have demonstrated outstanding performance. mRNA vaccines offer significant advantages over conventional vaccines in production speed and cost-effectiveness, making them an attractive option against other viral diseases. This article reviewed recent advances in viral mRNA vaccines and their delivery systems to provide references and guidance for developing mRNA vaccines for new viral diseases.
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Affiliation(s)
- Yukai Huang
- Department of Microbiology, School of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
| | - Xuerui Zhu
- Department of Microbiology, School of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
| | - Xiao Guo
- Department of Microbiology, School of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yuancheng Zhou
- Livestock and Poultry Biological Products Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu, China
| | - Dongying Liu
- Department of Microbiology, School of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
| | - Jingrui Mao
- Department of Microbiology, School of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yongai Xiong
- Department of Pharmaceutics, School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou, China
| | - Youcai Deng
- Department of Hematology, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing, China
| | - Xinghong Gao
- Department of Microbiology, School of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
- Provincial Department of Education, Key Laboratory of Infectious Disease & Bio-Safety, Zunyi Medical University, Zunyi, Guizhou, China
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19
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Calvisi DF, Boulter L, Vaquero J, Saborowski A, Fabris L, Rodrigues PM, Coulouarn C, Castro RE, Segatto O, Raggi C, van der Laan LJW, Carpino G, Goeppert B, Roessler S, Kendall TJ, Evert M, Gonzalez-Sanchez E, Valle JW, Vogel A, Bridgewater J, Borad MJ, Gores GJ, Roberts LR, Marin JJG, Andersen JB, Alvaro D, Forner A, Banales JM, Cardinale V, Macias RIR, Vicent S, Chen X, Braconi C, Verstegen MMA, Fouassier L. Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance. Nat Rev Gastroenterol Hepatol 2023; 20:462-480. [PMID: 36755084 DOI: 10.1038/s41575-022-00739-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/20/2022] [Indexed: 02/10/2023]
Abstract
Cholangiocarcinoma (CCA) is a rare malignancy that develops at any point along the biliary tree. CCA has a poor prognosis, its clinical management remains challenging, and effective treatments are lacking. Therefore, preclinical research is of pivotal importance and necessary to acquire a deeper understanding of CCA and improve therapeutic outcomes. Preclinical research involves developing and managing complementary experimental models, from in vitro assays using primary cells or cell lines cultured in 2D or 3D to in vivo models with engrafted material, chemically induced CCA or genetically engineered models. All are valuable tools with well-defined advantages and limitations. The choice of a preclinical model is guided by the question(s) to be addressed; ideally, results should be recapitulated in independent approaches. In this Consensus Statement, a task force of 45 experts in CCA molecular and cellular biology and clinicians, including pathologists, from ten countries provides recommendations on the minimal criteria for preclinical models to provide a uniform approach. These recommendations are based on two rounds of questionnaires completed by 35 (first round) and 45 (second round) experts to reach a consensus with 13 statements. An agreement was defined when at least 90% of the participants voting anonymously agreed with a statement. The ultimate goal was to transfer basic laboratory research to the clinics through increased disease understanding and to develop clinical biomarkers and innovative therapies for patients with CCA.
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Affiliation(s)
- Diego F Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Luke Boulter
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Cancer Research UK Scottish Centre, Institute of Genetics and Cancer, Edinburgh, UK
| | - Javier Vaquero
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Anna Saborowski
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Luca Fabris
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA
| | - Pedro M Rodrigues
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Cédric Coulouarn
- Inserm, Univ Rennes 1, OSS (Oncogenesis Stress Signalling), UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France
| | - Rui E Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Oreste Segatto
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Chiara Raggi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Luc J W van der Laan
- Department of Surgery, Erasmus MC Transplantation Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Benjamin Goeppert
- Institute of Pathology and Neuropathology, Ludwigsburg, Germany
- Institute of Pathology, Kantonsspital Baselland, Liestal, Switzerland
| | - Stephanie Roessler
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Timothy J Kendall
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Ester Gonzalez-Sanchez
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - John Bridgewater
- Department of Medical Oncology, UCL Cancer Institute, London, UK
| | - Mitesh J Borad
- Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, AZ, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Jose J G Marin
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Alejandro Forner
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Liver Unit, Barcelona Clinic Liver Cancer (BCLC) Group, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Jesus M Banales
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Rocio I R Macias
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Silve Vicent
- University of Navarra, Centre for Applied Medical Research, Program in Solid Tumours, Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC, Instituto de Salud Carlos III), Madrid, Spain
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
| | - Chiara Braconi
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Monique M A Verstegen
- Department of Surgery, Erasmus MC Transplantation Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Laura Fouassier
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
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Ai Y, Guo C, Garcia-Contreras M, Sanchez LS, Saftics A, Shodubi O, Raghunandan S, Xu J, Tsai SJ, Dong Y, Li R, Jovanovic-Talisman T, Gould S. Syntenin and CD63 Promote Exosome Biogenesis from the Plasma Membrane by Blocking Cargo Endocytosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.26.542409. [PMID: 37292617 PMCID: PMC10245948 DOI: 10.1101/2023.05.26.542409] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Exosomes are small extracellular vesicles important in health and disease. Syntenin is thought to drive the biogenesis of CD63 exosomes by recruiting Alix and the ESCRT machinery to endosomes, initiating an endosome-mediated pathway of exosome biogenesis. Contrary to this model, we show here that syntenin drives the biogenesis of CD63 exosomes by blocking CD63 endocytosis, thereby allowing CD63 to accumulate at the plasma membrane, the primary site of exosome biogenesis. Consistent with these results, we find that inhibitors of endocytosis induce the exosomal secretion of CD63, that endocytosis inhibits the vesicular secretion of exosome cargo proteins, and that high-level expression of CD63 itself also inhibits endocytosis. These and other results indicate that exosomes bud primarily from the plasma membrane, that endocytosis inhibits their loading into exosomes, that syntenin and CD63 are expression-dependent regulators of exosome biogenesis, and that syntenin drives the biogenesis of CD63 exosomes even in Alix knockout cells.
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21
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Parthasarathy G, Hirsova P, Kostallari E, Sidhu GS, Ibrahim SH, Malhi H. Extracellular Vesicles in Hepatobiliary Health and Disease. Compr Physiol 2023; 13:4631-4658. [PMID: 37358519 PMCID: PMC10798368 DOI: 10.1002/cphy.c210046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2023]
Abstract
Extracellular vesicles (EVs) are membrane-bound nanoparticles released by cells and are an important means of intercellular communication in physiological and pathological states. We provide an overview of recent advances in the understanding of EV biogenesis, cargo selection, recipient cell effects, and key considerations in isolation and characterization techniques. Studies on the physiological role of EVs have relied on cell-based model systems due to technical limitations of studying endogenous nanoparticles in vivo . Several recent studies have elucidated the mechanistic role of EVs in liver diseases, including nonalcoholic fatty liver disease, viral hepatitis, cholestatic liver disease, alcohol-associated liver disease, acute liver injury, and liver cancers. Employing disease models and human samples, the biogenesis of lipotoxic EVs downstream of endoplasmic reticulum stress and microvesicles via intracellular activation stress signaling are discussed in detail. The diverse cargoes of EVs including proteins, lipids, and nucleic acids can be enriched in a disease-specific manner. By carrying diverse cargo, EVs can directly confer pathogenic potential, for example, recruitment and activation of monocyte-derived macrophages in NASH and tumorigenicity and chemoresistance in hepatocellular carcinoma. We discuss the pathogenic role of EVs cargoes and the signaling pathways activated by EVs in recipient cells. We review the literature that EVs can serve as biomarkers in hepatobiliary diseases. Further, we describe novel approaches to engineer EVs to deliver regulatory signals to specific cell types, and thus use them as therapeutic shuttles in liver diseases. Lastly, we identify key lacunae and future directions in this promising field of discovery and development. © 2023 American Physiological Society. Compr Physiol 13:4631-4658, 2023.
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Affiliation(s)
| | - Petra Hirsova
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Guneet S. Sidhu
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Samar H. Ibrahim
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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22
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Jalil AT, Abdulhadi MA, Al-Ameer LR, Khaleel LA, Abdulameer SJ, Hadi AM, Merza MS, Zabibah RS, Ali A. Small but mighty: How microRNAs drive the deadly progression of cholangiocarcinoma. Pathol Res Pract 2023; 247:154565. [PMID: 37267725 DOI: 10.1016/j.prp.2023.154565] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 05/17/2023] [Accepted: 05/20/2023] [Indexed: 06/04/2023]
Abstract
Cholangiocarcinoma, also referred to as CCA, is a highly complex epithelial malignancy that can impact various organs and regions of the body, including the perihilar, intrahepatic, and distal organs. This cancer is characterized by the malignant growth of the epithelial lining in the bile ducts, which spans the entire biliary tree and is accountable for disease progression. The current state of affairs concerning CCA is concerning, with poor prognoses, high recurrence rates, and dismal long-term survival rates significantly burden healthcare facilities worldwide. Studies have identified numerous signaling pathways and molecules involved in the development and progression of CCA, including microRNAs, an important class of non-coding RNAs that have the ability to modulate these cellular signaling pathways significantly. In addition, microRNAs may serve as an innovative target for developing novel therapeutic approaches for CCA. In this review, we explore the underlying mechanisms and signaling pathways implicated in the initiation and progression of CCA, focusing on the future direction of utilizing microRNAs as a promising treatment option for this challenging malignancy.
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Affiliation(s)
| | - Mohanad Ali Abdulhadi
- Department of Medical Laboratory Techniques, Al-maarif University College, Al-Anbar, Iraq
| | | | - Luay Ali Khaleel
- College of Dentistry, National University of Science and Technology, Dhi Qar, Iraq
| | - Sada Jasim Abdulameer
- Biology Department, College of Education for Pure Science, Wasit University, Kut, Wasit, Iraq
| | | | - Muna S Merza
- Prosthetic dental Techniques Department, Al-Mustaqbal university College, Babylon, 51001, Iraq
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Ahmed Ali
- Medical technical college, Al-Farahidi University, Baghdad, Iraq
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23
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Han Q, Tan S, Gong L, Li G, Wu Q, Chen L, Du S, Li W, Liu X, Cai J, Wang Z. Omental cancer-associated fibroblast-derived exosomes with low microRNA-29c-3p promote ovarian cancer peritoneal metastasis. Cancer Sci 2023; 114:1929-1942. [PMID: 36644823 PMCID: PMC10154903 DOI: 10.1111/cas.15726] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 01/05/2023] [Accepted: 01/09/2023] [Indexed: 01/17/2023] Open
Abstract
Ovarian cancer (OC) is characterized by frequent widespread peritoneal metastasis. Cancer-associated fibroblasts (CAFs) represent a critical stromal component of metastatic niche and promote omentum metastasis in OC patients. However, the role of exosomes derived from omental CAFs in metastasis remains unclear. We isolated exosomes from primary omental normal fibroblasts (NFs) and CAFs from OC patients (NF-Exo and CAF-Exo, respectively) and assessed their effect on metastasis. In mice bearing orthotopic OC xenografts, CAF-Exo treatment led to more rapid intraperitoneal tumor dissemination and shorter animal survival. Similar results were observed in mice undergoing intraperitoneal injection of tumor cells. Among the miRNAs downregulated in CAF-Exo, miR-29c-3p in OC tissues was associated with metastasis and survival in patients. Moreover, increasing miR-29c-3p in CAF-Exo significantly weakened the metastasis-promoting effect of CAF-Exo. Based on RNA sequencing, expression assays, and luciferase assays, matrix metalloproteinase 2 (MMP2) was identified as a direct target of miR-29c-3p. These results verify the significant contribution of exosomes from omental CAFs to OC peritoneal metastasis, which could be partially due to the relief of MMP2 expression inhibition mediated by low exosomal miR-29c-3p.
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Affiliation(s)
- Qing Han
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- China Three Gorges University People's HospitalChina Three Gorges UniversityYichangChina
| | - Shuran Tan
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Lanqing Gong
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Guoqing Li
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Qiulei Wu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Le Chen
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Shi Du
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Wenhan Li
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xiaoli Liu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Jing Cai
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Zehua Wang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
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24
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Chen X, Ren X, E J, Zhou Y, Bian R. Exosome-transmitted circ IFNGR2 Modulates Ovarian Cancer Metastasis via miR-378/ST5 Axis. Mol Cell Biol 2023; 43:22-42. [PMID: 36720469 PMCID: PMC9937009 DOI: 10.1080/10985549.2022.2160605] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 12/05/2022] [Indexed: 01/28/2023] Open
Abstract
Cancer-associated fibroblasts (CAFs)-derived exosomes have emerged as a key driver of ovarian cancer (OVCA) tumor progression. The mechanisms behind the specific circular RNA (circRNA) activity encapsulated by CAF-generated exosomes (CAF-exo) requires to be elucidated. Herein, this study selected specific circRNA (hsa_circIFNGR2) molecules and aimed to clarify novel function of CAF-derived exosomal circIFNGR2 on growth, and metastasis of OVCA cells. In this study, we clarified that the exosomes of CAFs originating from human ovarian cancer hindered tumor cell proliferation, metastasis and EMT in vitro. Interestingly, CAFs directly transferred exosomes into OVCA cells to enrich intracellular circIFNGR2 levels. Biologically, activation of exosomal circIFNGR2 blocked cell proliferation, metastasis and EMT. Mechanistically, enhanced circIFNGR2 activated the miR-378/ST5 axis and directly inhibited the malignant evolution of tumor cells. Furthermore, rescue experiments evidenced that circIFNGR2 and ST5 were two essential participants in OVCA, concretely manifested in the co-culture of OVCA cells with exosomes that reversed the effects of intracellular circIFNGR2 and ST5 depletion. Finally, we observed that CAF-exo treatment hindered tumor growth and increased the size and number of metastatic nodules in mice. Our study revealed a previously unknown regulatory pathway whereby CAFs-derived exosomes delivered circIFNGR2 and inhibited the malignant progression of OVCA by circIFNGR2/miR-378/ST5 axis.
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Affiliation(s)
- Xiaoping Chen
- Obstetrics and Gynecology Department, Yancheng First People's Hospital, Yancheng, China
| | - Xinping Ren
- Obstetrics and Gynecology Department, Yancheng First People's Hospital, Yancheng, China
| | - Jiaoting E
- Obstetrics and Gynecology Department, Yancheng First People's Hospital, Yancheng, China
| | - Yaqi Zhou
- Obstetrics and Gynecology Department, Yancheng First People's Hospital, Yancheng, China
| | - Rongfang Bian
- Obstetrics and Gynecology Department, Yancheng First People's Hospital, Yancheng, China
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25
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Yedigaryan L, Martínez-Sarrà E, Giacomazzi G, Giarratana N, van der Veer BK, Rotini A, Querceto S, Grosemans H, Cortés-Calabuig Á, Salucci S, Battistelli M, Falcieri E, Gijsbers R, Quattrocelli M, Peng Koh K, De Waele L, Buyse GM, Derua R, Sampaolesi M. Extracellular vesicle-derived miRNAs improve stem cell-based therapeutic approaches in muscle wasting conditions. Front Immunol 2022; 13:977617. [PMID: 36451814 PMCID: PMC9702803 DOI: 10.3389/fimmu.2022.977617] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 10/17/2022] [Indexed: 11/15/2022] Open
Abstract
Skeletal muscle holds an intrinsic capability of growth and regeneration both in physiological conditions and in case of injury. Chronic muscle illnesses, generally caused by genetic and acquired factors, lead to deconditioning of the skeletal muscle structure and function, and are associated with a significant loss in muscle mass. At the same time, progressive muscle wasting is a hallmark of aging. Given the paracrine properties of myogenic stem cells, extracellular vesicle-derived signals have been studied for their potential implication in both the pathogenesis of degenerative neuromuscular diseases and as a possible therapeutic target. In this study, we screened the content of extracellular vesicles from animal models of muscle hypertrophy and muscle wasting associated with chronic disease and aging. Analysis of the transcriptome, protein cargo, and microRNAs (miRNAs) allowed us to identify a hypertrophic miRNA signature amenable for targeting muscle wasting, consisting of miR-1 and miR-208a. We tested this signature among others in vitro on mesoangioblasts (MABs), vessel-associated adult stem cells, and we observed an increase in the efficiency of myogenic differentiation. Furthermore, injections of miRNA-treated MABs in aged mice resulted in an improvement in skeletal muscle features, such as muscle weight, strength, cross-sectional area, and fibrosis compared to controls. Overall, we provide evidence that the extracellular vesicle-derived miRNA signature we identified enhances the myogenic potential of myogenic stem cells.
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Affiliation(s)
- Laura Yedigaryan
- Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Ester Martínez-Sarrà
- Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Giorgia Giacomazzi
- Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Nefele Giarratana
- Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Bernard K. van der Veer
- Department of Development and Regeneration, Laboratory for Stem Cell and Developmental Epigenetics, Stem Cell Institute, KU Leuven, Leuven, Belgium
| | - Alessio Rotini
- Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Silvia Querceto
- Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Hanne Grosemans
- Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Álvaro Cortés-Calabuig
- Laboratory for Cytogenetics and Genome Research, Department of Human Genetics, KU Leuven, Leuven, Belgium
| | - Sara Salucci
- Cellular Signalling Laboratory, Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
| | - Michela Battistelli
- Department of Biomolecular Sciences, Urbino University Carlo Bo, Urbino, Italy
| | - Elisabetta Falcieri
- Department of Biomolecular Sciences, Urbino University Carlo Bo, Urbino, Italy
| | - Rik Gijsbers
- Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, Leuven Viral Vector Core, KU Leuven, Leuven, Belgium
| | - Mattia Quattrocelli
- Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium,Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, Heart Institute, University of Cincinnati College of Medicine and Molecular Cardiovascular Biology Division, Cincinnati, OH, United States
| | - Kian Peng Koh
- Department of Development and Regeneration, Laboratory for Stem Cell and Developmental Epigenetics, Stem Cell Institute, KU Leuven, Leuven, Belgium
| | - Liesbeth De Waele
- Department of Development and Regeneration, Pediatric Neurology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Gunnar M. Buyse
- Department of Development and Regeneration, Pediatric Neurology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Rita Derua
- Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, SyBioMa, KU Leuven, Leuven, Belgium
| | - Maurilio Sampaolesi
- Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium,Histology and Medical Embryology Unit, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University of Rome, Rome, Italy,*Correspondence: Maurilio Sampaolesi,
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26
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Zhang X, Cao L, Xu G, He H, Zhao H, Liu T. Co-delivery of sorafenib and metformin from amphiphilic polypeptide-based micelles for colon cancer treatment. Front Med (Lausanne) 2022; 9:1009496. [PMID: 36304185 PMCID: PMC9592705 DOI: 10.3389/fmed.2022.1009496] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 08/12/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer (CRC) is a common clinical disease with a poor prognosis and a high recurrence rate. Chemotherapy is important to inhibit the post-surgical recurrence of CRC patients. But many limitations restrict the further application of chemotherapy. In this study, sorafenib (Sor) and metformin (Met) co-loaded poly(ethylene glycol)-block-poly(L-glutamic acid-co-L-phenylalanine) [mPEG-b-P(Glu-co-Phe)] micelles were developed. The characterizations, drug release, in vivo biodistribution, and pharmacokinetics of the micelles were analyzed. The treatment efficacy of the dual-drug loaded micelles was evaluated in a subcutaneous colon cancer mice model. Sor is a common molecular target agent that can inhibit the mitogen-activated protein kinase (MAPK) pathway to treat solid tumors. Met can also regulate the MAPK pathway and inhibit the expression of the phosphorylated extracellular signal-regulated kinase (p-ERK). Moreover, both Sor and Met play important roles in cell cycle arrest. The integration of these two drugs aims to achieve synergistic effects against colon cancer. The micelles can be targeted to cancer cells and possess longer blood circulation time. The two agents can be released rapidly in the tumor sites. The in vivo study showed that the micelles can prevent tumor progression by inhibiting the expressions of p-ERK and cyclin D1. This study indicated that the Sor/Met-loaded micelles are suitable for CRC treatment.
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Affiliation(s)
- Xiaohui Zhang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China,Department of Thyroid, Breast and Hernia Surgery, Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, China
| | - Lanqing Cao
- Department of Pathology, The Second Hospital of Jilin University, Changchun, China
| | - Guangmeng Xu
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Hongyu He
- Operating Theater and Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, China
| | - Hongyu Zhao
- Gastroenterology and Center of Digestive Endoscopy, The Second Hospital of Jilin University, Changchun, China,*Correspondence: Hongyu Zhao
| | - Tongjun Liu
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China,Tongjun Liu
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27
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Fordjour FK, Guo C, Ai Y, Daaboul GG, Gould SJ. A shared, stochastic pathway mediates exosome protein budding along plasma and endosome membranes. J Biol Chem 2022; 298:102394. [PMID: 35988652 PMCID: PMC9512851 DOI: 10.1016/j.jbc.2022.102394] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 08/14/2022] [Accepted: 08/16/2022] [Indexed: 11/19/2022] Open
Abstract
Exosomes are small extracellular vesicles of ∼30 to 150 nm that are secreted by all cells, abundant in all biofluids, and play important roles in health and disease. However, details about the mechanism of exosome biogenesis are unclear. Here, we carried out a cargo-based analysis of exosome cargo protein biogenesis in which we identified the most highly enriched exosomal cargo proteins and then followed their biogenesis, trafficking, and exosomal secretion to test different hypotheses for how cells make exosomes. We show that exosome cargo proteins bud from cells (i) in exosome-sized vesicles regardless of whether they are localized to plasma or endosome membranes, (ii) ∼5-fold more efficiently when localized to the plasma membrane, (iii) ∼5-fold less efficiently when targeted to the endosome membrane, (iv) by a stochastic process that leads to ∼100-fold differences in their abundance from one exosome to another, and (v) independently of small GTPase Rab27a, the ESCRT complex–associated protein Alix, or the cargo protein CD63. Taken together, our results demonstrate that cells use a shared, stochastic mechanism to bud exosome cargoes along the spectrum of plasma and endosome membranes and far more efficiently from the plasma membrane than the endosome. Our observations also indicate that the pronounced variation in content between different exosome-sized vesicles is an inevitable consequence of a stochastic mechanism of small vesicle biogenesis, that the origin membrane of exosome-sized extracellular vesicles simply cannot be determined, and that most of what we currently know about exosomes has likely come from studies of plasma membrane-derived vesicles.
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Affiliation(s)
- Francis K Fordjour
- Department of Biological Chemistry, Johns Hopkins University, Baltimore, MD, USA
| | - Chenxu Guo
- Department of Biological Chemistry, Johns Hopkins University, Baltimore, MD, USA
| | - Yiwei Ai
- Department of Biological Chemistry, Johns Hopkins University, Baltimore, MD, USA
| | | | - Stephen J Gould
- Department of Biological Chemistry, Johns Hopkins University, Baltimore, MD, USA.
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28
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Micro-RNA in Cholangiocarcinoma: Implications for Diagnosis, Prognosis, and Therapy. JOURNAL OF MOLECULAR PATHOLOGY 2022. [DOI: 10.3390/jmp3020009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Bile-duct cancers (BDC) are a group of solid tumors arising from the biliary tree. Despite their classification as rare cancers, the incidence of BDC is increasing worldwide. Poor prognosis is a common feature of this type of cancer and is mainly determined by the following factors: late diagnosis, lack of effective therapeutic approaches, and resistance to conventional treatments. In the past few years, next-generation sequencing technologies has allowed us to study the genome, exome, and transcriptome of BDC deeper, revealing a previously underestimated class of RNA: the noncoding RNA (ncRNA). MicroRNAs (miRNAs) are small ncRNAs that play an important regulatory role in gene expression. The aberrant expression of miRNAs and their pivotal role as oncogenes or tumor suppressors in biliary carcinogenesis has been widely described in BDC. Due to their ability to regulate multiple gene networks, miRNAs are involved in all cancer hallmarks, including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing/accessing vasculature, activating invasion and metastasis, reprogramming cellular metabolism, and avoiding immune destruction. Their use as diagnostic, prognostic, and predictive biomarkers has been widely explored in several human cancers, including BDC. Furthermore, miRNA-based therapeutic strategies are currently the subject of numerous clinical trials that are providing evidence of their efficacy as potent anticancer agents. In this review, we will provide a detailed update of miRNAs affecting BDC, discussing their regulatory function in processes underlying the molecular pathology of BDC. Finally, an overview of their potential use as biomarkers or therapeutic tools in BDC will be further addressed.
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29
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Gu J, Xu H, Chen Y, Li N, Hou X. MiR-223 as a Regulator and Therapeutic Target in Liver Diseases. Front Immunol 2022; 13:860661. [PMID: 35371024 PMCID: PMC8965842 DOI: 10.3389/fimmu.2022.860661] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 02/23/2022] [Indexed: 12/20/2022] Open
Abstract
MicroRNAs (miRNAs) are endogenous non-coding single-stranded small molecule RNAs consisting of 20–24 nucleotides that are highly conserved in species evolution. Expression of miRNAs is strictly tissue-specific, and it is chronological in fungi and plants, as well as in animals. MiR-223 has been shown to play a key role in innate immunity, and dysregulation of its expression contributes to the pathogenesis of multiple inflammatory diseases, and cancers. In this article the biosynthesis and functions of miR-223 in innate immunity are reviewed, and the role of miR-223 in liver physiopathology and therapeutic prospects are highlighted.
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Affiliation(s)
- Jiarong Gu
- School of Medicine, Ningbo University, Ningbo, China
| | - Hao Xu
- School of Medicine, Ningbo University, Ningbo, China
| | - Yandong Chen
- School of Medicine, Ningbo University, Ningbo, China
| | - Na Li
- School of Medicine, Ningbo University, Ningbo, China
| | - Xin Hou
- School of Medicine, Ningbo University, Ningbo, China.,The Affiliated Hospital of Medical School, Ningbo University, Ningbo, China
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30
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Pan Y, Tan WF, Yang MQ, Li JY, Geller DA. The therapeutic potential of exosomes derived from different cell sources in liver diseases. Am J Physiol Gastrointest Liver Physiol 2022; 322:G397-G404. [PMID: 35107032 PMCID: PMC8917924 DOI: 10.1152/ajpgi.00054.2021] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Exosomes are small nanovesicles with a size of approximately 40-120 nm that are secreted from cells. They are involved in the regulation of cell homeostasis and mediate intercellular communication. In addition, they carry proteins, nucleic acids, and lipids that regulate the biological activity of receptor cells. Recent studies have shown that exosomes perform important functions in liver diseases. This review will focus on liver diseases (drug-induced liver injury, hepatic ischemia-reperfusion injury, liver fibrosis, acute liver failure, and hepatocellular carcinoma) and summarize the therapeutic potential of exosomes from different cell sources in liver disease.
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Affiliation(s)
- Yun Pan
- 1Colorectal Cancer Center, Tenth People’s Hospital of Tongji University, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Wei-Feng Tan
- 2Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Mu-Qing Yang
- 3Department of General Surgery, Tenth People’s Hospital of Tongji University, Tongji University, Shanghai, People’s Republic of China
| | - Ji-Yu Li
- 3Department of General Surgery, Tenth People’s Hospital of Tongji University, Tongji University, Shanghai, People’s Republic of China
| | - David A. Geller
- 4Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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31
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Zhao K, Li X, Shi Y, Lu Y, Qiu P, Deng Z, Yao W, Wang J. Exosomes in the tumor microenvironment of cholangiocarcinoma: current status and future perspectives. J Transl Med 2022; 20:117. [PMID: 35255950 PMCID: PMC8900430 DOI: 10.1186/s12967-022-03294-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 02/02/2022] [Indexed: 11/24/2022] Open
Abstract
Cholangiocarcinoma (CCA) refers to an aggressive malignancy with a high fatality rate and poor prognosis. Globally, the morbidity of CCA is increasing for the past few decades, which has progressed into a disease that gravely endangers human health. Exosomes belong to a class of extracellular vesicles (EVs) with diameters ranging from 40 to 150 nm that can be discharged by all living cells. As communication messengers of the intercellular network, exosomes carry a diverse range of cargoes such as proteins, nucleic acids, lipids, and metabolic substances, which are capable of conveying biological information across different cell types to mediate various physiological activities or pathological changes. Increasing studies have demonstrated that exosomes in the tumor microenvironment participate in regulating tumorigenesis and progression via multiple approaches in the tumor microenvironment. Here, we reviewed the current research progress of exosomes in the context of cancer and particularly highlighted their functions in modulating the development of CCA. Furthermore, the potential values of exosomes as diagnostic and therapeutic targets in CCA were overviewed as well.
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Cholangiopathies and the noncoding revolution. Curr Opin Gastroenterol 2022; 38:128-135. [PMID: 35098934 DOI: 10.1097/mog.0000000000000806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
PURPOSE OF REVIEW Noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) among others, have attracted a great deal of attention for their potential role as master regulators of gene expression and as therapeutic targets. This review focuses on recent advances on the role of ncRNAs in the pathogenesis, diagnosis and treatment of diseases of the cholangiocytes (i.e. cholangiopathies). RECENT FINDINGS In the recent years, there has been an exponential growth in the knowledge on ncRNAs and their role in cholangiopathies, particularly cholangiocarcinoma. SUMMARY Although several studies focused on miRNAs as noninvasive biomarkers for diagnosis and staging, several studies also highlighted their functions and provided new insights into disease mechanisms.
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Driscoll J, Wehrkamp C, Ota Y, Thomas JN, Yan IK, Patel T. Biological Nanotherapeutics for Liver Disease. Hepatology 2021; 74:2863-2875. [PMID: 33825210 DOI: 10.1002/hep.31847] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/19/2021] [Accepted: 03/29/2021] [Indexed: 12/14/2022]
Abstract
Extracellular vesicles (EVs) are a heterogeneous group of biological nano-sized vesicles that are released from cells and contribute to intercellular communication. Emerging knowledge about their biogenesis, composition, release, and uptake has resulted in broad interest in elucidating their potential roles in disease pathophysiology. The distinct biological properties of these biological nanoparticles emphasize several appealing advantages for potential therapeutic applications compared with the use of synthetic nanoparticles. When administered systemically, EVs are taken up and sequestered within the liver, further emphasizing opportunities for therapeutic use. Consequently, there is growing interest in their use for liver diseases. EVs can be used directly as therapeutics, and several studies have highlighted the intrinsic therapeutic properties of mesenchymal stem cell-derived EVs for chronic and acute liver diseases. Alternatively, EVs can be modified to facilitate their use for the delivery of therapeutic cargo. In this review, we discuss the cellular sources of EV, provide a concise overview of their potential use in diverse processes, and outline several promising applications for the use of EV-based therapeutics for liver diseases. The use of EV-based therapeutics provides a viable approach to target hepatic pathophysiology.
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Affiliation(s)
- Julia Driscoll
- Department of Transplantation, Mayo Clinic, Jacksonville, FL
| | - Cody Wehrkamp
- Department of Transplantation, Mayo Clinic, Jacksonville, FL
| | - Yu Ota
- Department of Transplantation, Mayo Clinic, Jacksonville, FL
| | | | - Irene K Yan
- Department of Transplantation, Mayo Clinic, Jacksonville, FL
| | - Tushar Patel
- Department of Transplantation, Mayo Clinic, Jacksonville, FL
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Tsai SJ, Atai NA, Cacciottolo M, Nice J, Salehi A, Guo C, Sedgwick A, Kanagavelu S, Gould SJ. Exosome-mediated mRNA delivery in vivo is safe and can be used to induce SARS-CoV-2 immunity. J Biol Chem 2021; 297:101266. [PMID: 34600888 PMCID: PMC8483990 DOI: 10.1016/j.jbc.2021.101266] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 09/17/2021] [Accepted: 09/28/2021] [Indexed: 12/15/2022] Open
Abstract
Functional delivery of mRNA has high clinical potential. Previous studies established that mRNAs can be delivered to cells in vitro and in vivo via RNA-loaded lipid nanoparticles (LNPs). Here we describe an alternative approach using exosomes, the only biologically normal nanovesicle. In contrast to LNPs, which elicited pronounced cellular toxicity, exosomes had no adverse effects in vitro or in vivo at any dose tested. Moreover, mRNA-loaded exosomes were characterized by efficient mRNA encapsulation (∼90%), high mRNA content, consistent size, and a polydispersity index under 0.2. Using an mRNA encoding the red light-emitting luciferase Antares2, we observed that mRNA-loaded exosomes were superior to mRNA-loaded LNPs at delivering functional mRNA into human cells in vitro. Injection of Antares2 mRNA-loaded exosomes also led to strong light emission following injection into the vitreous fluid of the eye or into the tissue of skeletal muscle in mice. Furthermore, we show that repeated injection of Antares2 mRNA-loaded exosomes drove sustained luciferase expression across six injections spanning at least 10 weeks, without evidence of signal attenuation or adverse injection site responses. Consistent with these findings, we observed that exosomes loaded with mRNAs encoding immunogenic forms of the SARS-CoV-2 Spike and Nucleocapsid proteins induced long-lasting cellular and humoral responses to both. Taken together, these results demonstrate that exosomes can be used to deliver functional mRNA to and into cells in vivo.
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Affiliation(s)
- Shang Jui Tsai
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Nadia A Atai
- Capricor Therapeutics, Inc, Beverly Hills, California, USA
| | | | - Justin Nice
- Capricor Therapeutics, Inc, Beverly Hills, California, USA
| | - Arjang Salehi
- Capricor Therapeutics, Inc, Beverly Hills, California, USA
| | - Chenxu Guo
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | | | - Stephen J Gould
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
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He C, Wang L, Li L, Zhu G. Extracellular vesicle-orchestrated crosstalk between cancer-associated fibroblasts and tumors. Transl Oncol 2021; 14:101231. [PMID: 34601397 PMCID: PMC8493591 DOI: 10.1016/j.tranon.2021.101231] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 09/04/2021] [Accepted: 09/25/2021] [Indexed: 02/08/2023] Open
Abstract
EVs mediate the interaction between tumor and stromal cells in the TME. Tumors mediate CAF-like activation of stromal cells through EVs. CAF-derived EVs promote tumor proliferation, metastasis and therapeutic resistance. Communication networks in the tumor microenvironment (TME) play a crucial role in tumor progression. Cancer-associated fibroblasts (CAFs) are among the most abundant stromal cells in the TME. Bidirectional signal transduction between cancer cells and CAFs within the TME is important for cancer development and treatment responsiveness. Extracellular vesicles (EVs) carrying proteins, miRNAs, and other biomolecules are secreted into the extracellular matrix (ECM), which has been demonstrated to be an important communication medium between tumors and CAFs. Tumors regulate the activation of CAFs by secreting EVs. Conversely, CAFs can also affect tumor proliferation, metastasis, and therapeutic resistance through EVs. Here, we will classify EV cargoes and discuss the role of EV-mediated interactions between CAFs and tumors, reviewing current knowledge in combination with our confirmed results.
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Affiliation(s)
- Chuanshi He
- Department of Stomatology, Sichuan Cancer Hospital, Sichuan Key Laboratory of Radiation Oncology, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Linlin Wang
- Department of Stomatology, Sichuan Cancer Hospital, Sichuan Key Laboratory of Radiation Oncology, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Ling Li
- Department of Stomatology, Sichuan Cancer Hospital, Sichuan Key Laboratory of Radiation Oncology, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Guiquan Zhu
- State Key Laboratory of Oral Diseases, National Clinical Research Centre for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Chengdu, Sichuan 610041, China.
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Ota Y, Takahashi K, Otake S, Tamaki Y, Okada M, Yan I, Aso K, Fujii S, Patel T, Haneda M. Extracellular RNA transfer from non-malignant human cholangiocytes can promote cholangiocarcinoma growth. FEBS Open Bio 2021; 11:3276-3292. [PMID: 34510808 PMCID: PMC8634862 DOI: 10.1002/2211-5463.13294] [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: 04/24/2021] [Revised: 08/07/2021] [Accepted: 09/09/2021] [Indexed: 11/12/2022] Open
Abstract
Extracellular vesicles (EV) within the cellular secretome are emerging as modulators of pathological processes involved in tumor growth through their ability to transfer donor‐derived RNA into recipient cells. While the effects of tumor and stromal cell EVs within the tumor microenvironment have been studied, less is known about the contributions of normal, nontransformed cells. We examined the impact of EVs within the cellular secretome from nonmalignant cells on transformed cell growth and behavior in cholangiocarcinoma cells. These effects were enhanced in the presence of the pro‐fibrogenic mediator TGF‐β. We identified miR‐195 as a TGF‐β responsive miRNA in normal cells that can be transferred via EV to tumor cells and regulate cell growth, invasion, and migration. The effects of miR‐195 involve modulation of the epithelial–mesenchymal transition through direct effects on the transcription factor Snail. These studies provide in vitro and in vivo evidence for the impact of normal cellular secretome on transformed cell growth, show the importance of EV RNA transfer, and identify mechanisms of EV‐mediated transfer of miRNA as a contributor to tumor development, which may provide new therapeutic opportunities for targeting human cholangiocarcinoma.
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Affiliation(s)
- Yu Ota
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan
| | - Kenji Takahashi
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan
| | - Shin Otake
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan
| | - Yosui Tamaki
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan
| | - Mitsuyoshi Okada
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan
| | - Irene Yan
- Departments of Transplantation and Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
| | - Kazunobu Aso
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan
| | - Satoshi Fujii
- Department of Laboratory Medicine, Asahikawa Medical University, Japan
| | - Tushar Patel
- Departments of Transplantation and Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
| | - Masakazu Haneda
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan
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Zheng W, Ji D, Zhou Y, Yu L, Huang P, Zheng Y, Meng N, Wang H, Bai X, Huang Z, Chen W, Yam JWP, Xu Y, Cui Y. Exosomal non-coding RNAs in Hepatobiliary Cancer: A Rising Star. Mol Cancer Ther 2021; 20:1777-1788. [PMID: 34376575 DOI: 10.1158/1535-7163.mct-21-0363] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 06/24/2021] [Accepted: 08/04/2021] [Indexed: 11/16/2022]
Abstract
Hepatobiliary cancers are a heterogeneous group of malignancies with a dismal prognosis. Despite intensive research efforts focused on these tumors, methods for early diagnosis and effective targeted therapies are still lacking. Exosomes, released by most cells, exist in all kinds of body fluids and play an important role in cell-to-cell communication. They are small membranous vesicles containing biological molecules, such as noncoding RNAs (ncRNAs), which are not translated into proteins, but they exert effects on the regulation of gene transcription and translation. There is growing evidence for the essential roles of ncRNAs in exosomes in both physiological and pathological conditions of hepatobiliary cancers. They have been identified as sensitive diagnostic biomarkers as well as potential therapeutic targets. The present review discusses recent findings in the crosstalk between hepatobiliary cancers cells and the surrounding cells of the microenvironment and discuss their potential clinical usage.
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Affiliation(s)
- Wangyang Zheng
- Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University
| | - Daolin Ji
- Forth Affiliated Hospital of Harbin Medical University
| | - Yongxu Zhou
- Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University
| | - Liang Yu
- Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University
| | - Peng Huang
- Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University
| | - Yuling Zheng
- Department of Pediatric, Second Affiliated Hospital of Harbin Medical University
| | - Nanfeng Meng
- Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University
| | - Hang Wang
- Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University
| | - Xue Bai
- Department of Renal Cancer and Melanoma/Cancer Center, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute/Massachusetts General Hospital
| | - ZiYue Huang
- Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University
| | - Wangming Chen
- Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University
| | - Judy W P Yam
- Department of Pathology, University of Hong Kong
| | - Yi Xu
- Department of Pathology, University of Hong Kong
| | - Yunfu Cui
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University
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Kostallari E, Valainathan S, Biquard L, Shah VH, Rautou PE. Role of extracellular vesicles in liver diseases and their therapeutic potential. Adv Drug Deliv Rev 2021; 175:113816. [PMID: 34087329 PMCID: PMC10798367 DOI: 10.1016/j.addr.2021.05.026] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/17/2021] [Accepted: 05/29/2021] [Indexed: 02/07/2023]
Abstract
More than eight hundred million people worldwide have chronic liver disease, with two million deaths per year. Recurring liver injury results in fibrogenesis, progressing towards cirrhosis, for which there doesn't exists any cure except liver transplantation. Better understanding of the mechanisms leading to cirrhosis and its complications is needed to develop effective therapies. Extracellular vesicles (EVs) are released by cells and are important for cell-to-cell communication. EVs have been reported to be involved in homeostasis maintenance, as well as in liver diseases. In this review, we present current knowledge on the role of EVs in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, alcohol-associated liver disease, chronic viral hepatitis, primary liver cancers, acute liver injury and liver regeneration. Moreover, therapeutic strategies involving EVs as targets or as tools to treat liver diseases are summarized.
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Affiliation(s)
- Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States.
| | - Shantha Valainathan
- Université de Paris, AP-HP, Hôpital Beaujon, Service d'Hépatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Centre de recherche sur l'inflammation, Inserm, UMR 1149, Paris, France
| | - Louise Biquard
- Université de Paris, Centre de recherche sur l'inflammation, Inserm, UMR 1149, Paris, France.
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States.
| | - Pierre-Emmanuel Rautou
- Université de Paris, AP-HP, Hôpital Beaujon, Service d'Hépatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Centre de recherche sur l'inflammation, Inserm, UMR 1149, Paris, France.
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Qin X, Lu M, Li G, Zhou Y, Liu Z. Downregulation of tumor-derived exosomal miR-34c induces cancer-associated fibroblast activation to promote cholangiocarcinoma progress. Cancer Cell Int 2021; 21:373. [PMID: 34261453 PMCID: PMC8278610 DOI: 10.1186/s12935-020-01726-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 12/19/2020] [Indexed: 12/31/2022] Open
Abstract
Background This study aimed to investigate the exact regulatory mechanisms of exosomal miR-34c in mediating communication between cholangiocarcinoma cells and fibroblasts. Methods Exosomes were isolated from HuCCT-1 and HIBEC cells using differential ultracentrifugation and identified by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) method. Real-time quantitative PCR (qRT-PCR) and western blotting analyses were performed to assess the levels of pro-inflammatory factors, and fibroblast-related proteins and Wnt-linked signaling pathway proteins, respectively. Exosome-tracking was performed with confocal microscopy. The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and Transwell assays were used to measure cell proliferation and migration, respectively. Further, the oncogenicity of cholangiocarcinoma cells was analyzed in nude mice transplanted tumor model. Results The analysis suggested that the expression of miR-34c was decreased in exosomes from HuCCT-1 cells. Moreover, miR-34c in exosomes mediated fibroblast activation by directly targeting WNT1. Additionally, cancer-associated fibroblasts (CAFs) activated by downregulation of exosomal miR-34c promoted cholangiocarcinoma progression. Conclusions Thus, miR-34c in exosomes was found to be a key player in regulating intercellular communication between tumor cells and fibroblasts.
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Affiliation(s)
- Xinglei Qin
- Department of Hepatobiliary Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, No.7 Weiwu Road, Zhengzhou, Henan, 450003, China.
| | - Min Lu
- Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, 450003, China
| | - Gang Li
- Department of Hepatobiliary Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, No.7 Weiwu Road, Zhengzhou, Henan, 450003, China
| | - Yajun Zhou
- Department of Hepatobiliary Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, No.7 Weiwu Road, Zhengzhou, Henan, 450003, China
| | - Zhaoyang Liu
- Department of Hepatobiliary Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, No.7 Weiwu Road, Zhengzhou, Henan, 450003, China
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Zhang M, Xian HC, Dai L, Tang YL, Liang XH. MicroRNAs: emerging driver of cancer perineural invasion. Cell Biosci 2021; 11:117. [PMID: 34187567 PMCID: PMC8243427 DOI: 10.1186/s13578-021-00630-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 06/14/2021] [Indexed: 02/07/2023] Open
Abstract
The perineural invasion (PNI), which refers to tumor cells encroaching on nerve, is a clinical feature frequently occurred in various malignant tumors, and responsible for postoperative recurrence, metastasis and decreased survival. The pathogenesis of PNI switches from 'low-resistance channel' hypothesis to 'mutual attraction' theory between peripheral nerves and tumor cells in perineural niche. Among various molecules in perineural niche, microRNA (miRNA) as an emerging modulator of PNI through generating RNA-induced silencing complex (RISC) to orchestrate oncogene and anti-oncogene has aroused a wide attention. This article systematically reviewed the role of microRNA in PNI, promising to identify new biomarkers and offer cancer therapeutic targets.
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Affiliation(s)
- Mei Zhang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology (Sichuan University), No.14, Sec. 3, Renminnan Road, Chengdu, 610041, China
| | - Hong-Chun Xian
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Pathology, West China Hospital of Stomatology (Sichuan University), No.14, Sec. 3, Renminnan Road, Chengdu, 610041, China
| | - Li Dai
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology (Sichuan University), No.14, Sec. 3, Renminnan Road, Chengdu, 610041, China
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Pathology, West China Hospital of Stomatology (Sichuan University), No.14, Sec. 3, Renminnan Road, Chengdu, 610041, China.
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology (Sichuan University), No.14, Sec. 3, Renminnan Road, Chengdu, 610041, China.
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The Emerging Role of Immunotherapy in Intrahepatic Cholangiocarcinoma. Vaccines (Basel) 2021; 9:vaccines9050422. [PMID: 33922362 PMCID: PMC8146949 DOI: 10.3390/vaccines9050422] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/18/2021] [Accepted: 04/20/2021] [Indexed: 12/17/2022] Open
Abstract
Biliary tract cancer, and intrahepatic cholangiocarcinoma (iCC) in particular, represents a rather uncommon, highly aggressive malignancy with unfavorable prognosis. Therapeutic options remain scarce, with platinum-based chemotherapy is being considered as the gold standard for the management of advanced disease. Comprehensive molecular profiling of tumor tissue biopsies, utilizing multi-omics approaches, enabled the identification of iCC’s intratumor heterogeneity and paved the way for the introduction of novel targeted therapies under the scope of precision medicine. Yet, the unmet need for optimal care of patients with chemo-refractory disease or without targetable mutations still exists. Immunotherapy has provided a paradigm shift in cancer care over the past decade. Currently, immunotherapeutic strategies for the management of iCC are under intense research. Intrinsic factors of the tumor, including programmed death-ligand 1 (PD-L1) expression and mismatch repair (MMR) status, are simply the tip of the proverbial iceberg with regard to resistance to immunotherapy. Acknowledging the significance of the tumor microenvironment (TME) in both cancer growth and drug response, we broadly discuss about its diverse immune components. We further review the emerging role of immunotherapy in this rare disease, summarizing the results of completed and ongoing phase I–III clinical trials, expounding current challenges and future directions.
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Wang X, He Y, Mackowiak B, Gao B. MicroRNAs as regulators, biomarkers and therapeutic targets in liver diseases. Gut 2021; 70:784-795. [PMID: 33127832 DOI: 10.1136/gutjnl-2020-322526] [Citation(s) in RCA: 286] [Impact Index Per Article: 71.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/01/2020] [Accepted: 10/09/2020] [Indexed: 12/11/2022]
Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression by binding to specific mRNA targets and promoting their degradation and/or translational inhibition. miRNAs regulate both physiological and pathological liver functions. Altered expression of miRNAs is associated with liver metabolism dysregulation, liver injury, liver fibrosis and tumour development, making miRNAs attractive therapeutic strategies for the diagnosis and treatment of liver diseases. Here, we review recent advances regarding the regulation and function of miRNAs in liver diseases with a major focus on miRNAs that are specifically expressed or enriched in hepatocytes (miR-122, miR-194/192), neutrophils (miR-223), hepatic stellate cells (miR-29), immune cells (miR-155) and in circulation (miR-21). The functions and target genes of these miRNAs are emphasised in alcohol-associated liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, viral hepatitis and hepatocellular carcinoma, as well liver fibrosis and liver failure. We touch on the roles of miRNAs in intercellular communication between hepatocytes and other types of cells via extracellular vesicles in the pathogenesis of liver diseases. We provide perspective on the application of miRNAs as biomarkers for early diagnosis, prognosis and assessment of liver diseases and discuss the challenges in miRNA-based therapy for liver diseases. Further investigation of miRNAs in the liver will help us better understand the pathogeneses of liver diseases and may identify biomarkers and therapeutic targets for liver diseases in the future.
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Affiliation(s)
- Xiaolin Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Yong He
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Bryan Mackowiak
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
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Wang J, Ilyas S. Targeting the tumor microenvironment in cholangiocarcinoma: implications for therapy. Expert Opin Investig Drugs 2021; 30:429-438. [PMID: 33322977 PMCID: PMC8096665 DOI: 10.1080/13543784.2021.1865308] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 12/14/2020] [Indexed: 02/08/2023]
Abstract
Introduction: Cholangiocarcinomas (CCAs) are biliary epithelial tumors with rising incidence over the past 3 decades. Early diagnosis of CCAs remains a significant challenge and the majority of patients present at an advanced stage. CCAs are heterogeneous tumors and currently available standard systemic therapy options are of limited effectiveness. Immune checkpoint inhibition (ICI) has transformed cancer therapy across a spectrum of malignancies. However, the response rate to ICI has been relatively disappointing in CCAs owing to its desmoplastic tumor microenvironment (TME).Areas covered: Tumor microenvironment of CCAs consists of innate and adaptive cells, stromal cells, and extracellular components (cytokines, chemokines, exosomes, etc.). This intricate microenvironment has multiple immunosuppressive elements that promote tumor cell survival and therapeutic resistance. Accordingly, there is a need for the development of effective therapeutic strategies that target the TME. Herein, we review the components of the CCA TME, and potential therapies targeting the CCA TME.Expert opinion: CCAs are desmoplastic tumors with a dense tumor microenvironment. An enhanced understanding of the various components of the CCA TME is essential in the effort to develop novel biomarkers for patient stratification as well as combination therapeutic strategies that target the tumor plus the TME.
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Affiliation(s)
- Juan Wang
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Sumera Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Hepatic stellate cells promote intrahepatic cholangiocarcinoma progression via NR4A2/osteopontin/Wnt signaling axis. Oncogene 2021; 40:2910-2922. [PMID: 33742120 DOI: 10.1038/s41388-021-01705-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 01/26/2021] [Accepted: 02/08/2021] [Indexed: 12/13/2022]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a highly fatal malignancy characterized by a vast amount of intra-tumoral fibroblasts. These fibroblasts are potentially implicated in maintaining the high aggressiveness of ICC, whereas its pro-cancer mechanisms remain scarcely reported. Here, by establishing co-culture models of ICC cells and hepatic stellate cells (HSCs), we identified that HSCs triggered the expression of nuclear receptor family 4 subgroup A member 2 (NR4A2), a transcription factor previously reported as a molecular switch between inflammation and cancer, in ICC cells. Functionally, NR4A2 promotes tumor proliferation, metastatic potentiality and represents an independent prognostic indicator for overall survival in ICC patients. Mechanistically, NR4A2 upregulates osteopontin (OPN) expression through transcriptional activation and thereby augments the activity of Wnt/β-catenin signaling. Intriguingly, in the context of co-culture, vascular endothelial growth factor (VEGF), a previously proved NR4A2 stimulus, not only enhances NR4A2 expression, but also can be blunted by the interference of the NR4A2-OPN axis. Altogether, this study suggests the NR4A2/OPN/Wnt signaling axis to be a pivotal executor of HSC-instigated cancer-promoting roles in ICC, and the NR4A2/OPN/VEGF positive feedback loop may help to reinforce the effect.
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Wang Z, Yang Q, Tan Y, Tang Y, Ye J, Yuan B, Yu W. Cancer-Associated Fibroblasts Suppress Cancer Development: The Other Side of the Coin. Front Cell Dev Biol 2021; 9:613534. [PMID: 33614646 PMCID: PMC7890026 DOI: 10.3389/fcell.2021.613534] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 01/15/2021] [Indexed: 12/16/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs) are the main stromal components of cancer, representing a group of heterogeneous cells. Many studies indicate that CAFs promote tumor development. Besides, evidence of the tumor suppression effects of CAFs keeps on merging. In the tumor microenvironment, multiple stimuli can activate fibroblasts. Notably, this does not necessarily mean the activated CAFs become strong tumor promoters immediately. The varying degree of CAFs activation makes quiescent CAFs, tumor-restraining CAFs, and tumor-promoting CAFs. Quiescent CAFs and tumor-restraining CAFs are more present in early-stage cancer, while comparatively, more tumor-promoting CAFs present in advanced-stage cancer. The underlying mechanism that balances tumor promotion or tumor inhibition effects of CAFs is mostly unknown. This review focus on the inhibitory effects of CAFs on cancer development. We describe the heterogeneous origin, markers, and metabolism in the CAFs population. Transgenetic mouse models that deplete CAFs or deplete CAFs activation signaling in the tumor stroma present direct evidence of CAFs protective effects against cancer. Moreover, we outline CAFs subpopulation and CAFs derived soluble factors that act as a tumor suppressor. Single-cell RNA-sequencing on CAFs population provides us new insight to classify CAFs subsets. Understanding the full picture of CAFs will help translate CAFs biology from bench to bedside and develop new strategies to improve precision cancer therapy.
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Affiliation(s)
- Zhanhuai Wang
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qi Yang
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yinuo Tan
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yang Tang
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Ye
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bin Yuan
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, United States
| | - Wei Yu
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Wu H, Zhou X, Wang X, Cheng W, Hu X, Wang Y, Luo B, Huang W, Gu J. miR-34a in extracellular vesicles from bone marrow mesenchymal stem cells reduces rheumatoid arthritis inflammation via the cyclin I/ATM/ATR/p53 axis. J Cell Mol Med 2021; 25:1896-1910. [PMID: 33465281 PMCID: PMC7882978 DOI: 10.1111/jcmm.15857] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 07/31/2020] [Accepted: 08/21/2020] [Indexed: 12/14/2022] Open
Abstract
Extracellular vesicles (Evs) participate in the development of rheumatoid arthritis (RA), but the mechanisms remain unclear. This study aimed to determine the mechanism by which microRNA‐34a (miR‐34a) contained in bone marrow mesenchymal stem cell (BM‐MSC)‐derived Evs functions in RA fibroblast‐like synoviocytes (RA‐FLSs). BM‐MSC‐derived Evs and an Evs inhibitor were extracted. A rat model of RA was established. miR‐34a gain‐ and loss‐of‐function experiments were performed, and the inflammation in rat synovial fluid and tissues was detected. The role of miR‐34a in RA‐FLSs was also measured in vitro. The target gene of miR‐34a was predicted using the online software TargetScan and identified using a dual‐luciferase reporter gene assay, and the activation of the ATM/ATR/p53 signalling pathway was assessed. BM‐MSC‐derived Evs mainly elevated miR‐34a expression, which reduced RA inflammation in vivo and inhibited RA‐FLS proliferation and resistance to apoptosis in vitro, while inhibited miR‐34a expression enhanced RA development. In addition, miR‐34a could target cyclin I to activate the ATM/ATR/p53 signalling pathway, thus inhibiting abnormal RA‐FLS growth and RA inflammation. Our study showed that miR‐34a contained in BM‐MSC‐derived Evs could reduce RA inflammation by inhibiting the cyclin I/ATM/ATR/p53 signalling pathway.
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Affiliation(s)
- Huaiguo Wu
- Center for Precision Medicine, Anhui No. 2 Provincial People's Hospital, Hefei, China
| | - Xike Zhou
- Department of Medical Laboratory Science, The Fifth People's Hospital of Wuxi, Nanjing Medical University, Wuxi, China.,Department of Pathology, The Fifth People's Hospital of Wuxi, The Medical School of Jiangnan University, Wuxi, China
| | - Xuedong Wang
- Center for Precision Medicine, Anhui No. 2 Provincial People's Hospital, Hefei, China.,Department of Medical Laboratory Science, The Fifth People's Hospital of Wuxi, Nanjing Medical University, Wuxi, China
| | - Wei Cheng
- Center for Precision Medicine, Anhui No. 2 Provincial People's Hospital, Hefei, China
| | - Xinjia Hu
- Center for Precision Medicine, Anhui No. 2 Provincial People's Hospital, Hefei, China.,Department of Osteoarthropathy, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University and the First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
| | - Yueping Wang
- Center for Precision Medicine, Anhui No. 2 Provincial People's Hospital, Hefei, China.,Department of Medical Laboratory Science, The Fifth People's Hospital of Wuxi, Nanjing Medical University, Wuxi, China.,Department of Biology, College of Arts & Science, Massachusetts University, Boston, MA, USA
| | - Bing Luo
- Center for Precision Medicine, Anhui No. 2 Provincial People's Hospital, Hefei, China.,Department of Medical Laboratory Science, The Fifth People's Hospital of Wuxi, Nanjing Medical University, Wuxi, China
| | - Wenjun Huang
- Center for Precision Medicine, Anhui No. 2 Provincial People's Hospital, Hefei, China.,Department of Osteoarthropathy, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University and the First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
| | - Juan Gu
- Department of Medical Laboratory Science, The Fifth People's Hospital of Wuxi, Nanjing Medical University, Wuxi, China.,Department of Pathology, The Fifth People's Hospital of Wuxi, The Medical School of Jiangnan University, Wuxi, China
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Roles of Bile-Derived Exosomes in Hepatobiliary Disease. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8743409. [PMID: 33511212 PMCID: PMC7822672 DOI: 10.1155/2021/8743409] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 12/23/2020] [Accepted: 01/06/2021] [Indexed: 12/14/2022]
Abstract
Exosomes are vesicles with a diameter of 30-150 nm produced by living cells and secreted into the extracellular matrix. Exosomes mediate cellular communication by carrying active molecules, such as nucleic acids, proteins, and liposomes. Although exosomes are found in various body fluids, little is known about bile-derived exosomes. This review is the first to summarize the methods of bile storage and isolation of biliary exosomes, highlighting the roles of bile-derived exosomes, especially exosomal noncoding RNAs, in physiological and disease states and discussing their potential clinical applications.
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Small extracellular vesicles containing miR-30a-3p attenuate the migration and invasion of hepatocellular carcinoma by targeting SNAP23 gene. Oncogene 2021; 40:233-245. [PMID: 33110233 DOI: 10.1038/s41388-020-01521-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 10/03/2020] [Accepted: 10/13/2020] [Indexed: 02/07/2023]
Abstract
Cancer cells under hypoxic, endoplasmic reticulum, and reactive oxygen species stress secrete copious amounts of small extracellular vesicles (sEVs) to promote tumor metastasis. The effects of blocking stress-induced sEV release on tumor metastasis remain unknown. We found that miR-30a-3p was selectively sorted into sEVs by hepatocellular carcinoma (HCC) cells under the influence of multiple stressors. miR-30a-3p removal from cancer cells through sEVs promoted HCC cell migration and invasion, whereas exogenous overexpression of miR-30a-3p could inhibit migration, invasion, and sEV release by directly targeting SNAP23. HCC cells efficiently absorbed hepatic stellate cell (HSC) sEVs, providing an advantage in the treatment of HCC using HSC sEVs. Treatment with HSC sEVs rich in miR-30a-3p cargo effectively attenuated HCC migration, invasion, and metastasis. Overall, sEVs containing miR-30a-3p decreased sEV secretion as well as the migration, invasion, and metastasis of HCC by directly targeting SNAP23, thereby providing an effective strategy to attenuate metastasis of HCC.
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Fabris L, Sato K, Alpini G, Strazzabosco M. The Tumor Microenvironment in Cholangiocarcinoma Progression. Hepatology 2021; 73 Suppl 1:75-85. [PMID: 32500550 PMCID: PMC7714713 DOI: 10.1002/hep.31410] [Citation(s) in RCA: 139] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 05/07/2020] [Accepted: 05/16/2020] [Indexed: 12/15/2022]
Abstract
Cholangiocarcinoma (CCA) is an aggressive and heterogeneous malignancy of the biliary tree. A typical hallmark of CCA is that cancer cells are embedded into a dense stroma containing fibrogenic cells, lymphatics and a variety of immune cells. Functional roles of the reactive tumor stroma are not fully elucidated; however, recent studies suggest that the tumor microenvironment plays a key role in the progression and invasiveness of CCA. CCA cells exchange autocrine/paracrine signals with other cancer cells and the infiltrating cell types that populate the microenvironment. This crosstalk is under the control of signals mediated by various cytokines, chemokines, and growth factors. In addition, extracellular vesicles (EVs), exosomes and microvesicles, containing cargo mediators, such as proteins and RNAs, play a key role in cell-to-cell communication, and particularly in epigenetic regulation thanks to their content in miRNAs. Both cytokine- and EV-mediated communications between CCA cells and other liver cells provide a potential novel target for the management of CCA. This review summarizes current understandings of the tumor microenvironment and intercellular communications in CCA and their role in tumor progression.
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Affiliation(s)
- Luca Fabris
- Department of Molecular Medicine, University of Padua, Padua, Italy,Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT
| | - Keisaku Sato
- Hepatology and Gastroenterology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Gianfranco Alpini
- Hepatology and Gastroenterology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN,Richard L. Roudebush VA Medical Center, Indianapolis, IN
| | - Mario Strazzabosco
- Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT,Correspondence: Mario Strazzabosco MD, PhD, Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA,
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50
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Shi T, Gong J, Fujita K, Nishiyama N, Iwama H, Liu S, Nakahara M, Yoneyama H, Morishita A, Nonura T, Kobara H, Okano K, Suzuki Y, Masaki T. Aspirin inhibits cholangiocarcinoma cell proliferation via cell cycle arrest in vitro and in vivo. Int J Oncol 2020; 58:199-210. [PMID: 33491760 PMCID: PMC7864011 DOI: 10.3892/ijo.2020.5165] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 10/23/2020] [Indexed: 12/21/2022] Open
Abstract
Cholangiocarcinoma is the most common biliary duct malignancy and the second most common primary liver cancer, accounting for 10-20% of hepatic malignancies. With high mortality and poor prognosis, the 5-year survival rate of cholangiocarcinoma is only 10%. A previous study demonstrated a significant association between aspirin use and a decreased risk of cholangiocarcinoma. However, the effect of aspirin on cholangiocarcinoma remains unknown. Therefore, the aim of the present study was to investigate the effects of aspirin on cholangiocarcinoma in vitro and in vivo. Three cholangiocarcinoma cell lines were used to analyze the effect of aspirin on cell proliferation, cell cycle progression, apoptosis, and the regulation of microRNAs. MicroRNAs are known to regulate the development and progression of various types of cancer. An HuCCT-1 xenograft model was used for the in vivo study. It was determined that aspirin inhibited the proliferation of human cholangiocarcinoma cells (except TKKK cells). Aspirin induced cell cycle arrest in the G0/G1 phase and regulated cell-cycle related proteins in cholangiocarcinoma cells (HuCCT-1 cells) but did not induce apoptosis. The expression of miR-340-5p was significantly upregulated after treatment, and overexpression of miR-340-5p inhibited the proliferation of HuCCT-1 cells and decreased the levels of cyclin D1. TKKK cells had low miR-340-5p expression, which may explain why aspirin had no effect on their proliferation. In vivo, aspirin reduced the growth of xenografted tumors. In conclusion, the present study indicated that aspirin partially inhibited cholangiocarcinoma cell proliferation and tumor growth by inducing G0/G1 phase cell cycle arrest, potentially through the miR-340-5p/cyclin D1 axis.
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Affiliation(s)
- Tingting Shi
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Jian Gong
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Noriko Nishiyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Hisakazu Iwama
- Life Science Research Center, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Shi Liu
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Takako Nonura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Keiichi Okano
- Department of Digestive Surgery, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Yasuyuki Suzuki
- Department of Digestive Surgery, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
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