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Jiramonai L, Liang XJ, Zhu M. Extracellular Vesicle-Based Strategies for Tumor Immunotherapy. Pharmaceutics 2025; 17:257. [PMID: 40006624 PMCID: PMC11859549 DOI: 10.3390/pharmaceutics17020257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/26/2025] [Accepted: 02/12/2025] [Indexed: 02/27/2025] Open
Abstract
Immunotherapy is one of the most promising approaches for cancer management, as it utilizes the intrinsic immune response to target cancer cells. Normally, the human body uses its immune system as a defense mechanism to detect and eliminate foreign objects, including cancer cells. However, cancers develop a 'switch off' mechanism, known as immune checkpoint proteins, to evade immune surveillance and suppress immune activation. Therefore, significant efforts have been made to develop the strategies for stimulating immune responses against cancers. Among these, the use of extracellular vesicles (EVs) to enhance the anti-tumor immune response has emerged as a particularly promising approach in cancer management. EVs possess several unique properties that elevate the potency in modulating immune responses. This review article provides a comprehensive overview of recent advances in this field, focusing on the strategic usage of EVs to overcome tumor-induced immune tolerance. We discuss the biogenesis and characteristics of EVs, as well as their potential applications in medical contexts. The immune mechanisms within the tumor microenvironment and the strategies employed by cancers to evade immune detection are explored. The roles of EVs in regulating the tumor microenvironment and enhancing immune responses for immunotherapy are also highlighted. Additionally, this article addresses the challenges and future directions for the development of EV-based nanomedicine approaches, aiming to improve cancer immunotherapy outcomes with greater precision and efficacy while minimizing off-target effects.
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Affiliation(s)
- Luksika Jiramonai
- Chinese Academy of Sciences (CAS), Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China;
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xing-Jie Liang
- Chinese Academy of Sciences (CAS), Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China;
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Mengliang Zhu
- Chinese Academy of Sciences (CAS), Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China;
- University of Chinese Academy of Sciences, Beijing 100049, China
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2
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Qiu L, Ma Z, Wu X. Mutant p53-Mediated Tumor Secretome: Bridging Tumor Cells and Stromal Cells. Genes (Basel) 2024; 15:1615. [PMID: 39766882 PMCID: PMC11675497 DOI: 10.3390/genes15121615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 12/06/2024] [Accepted: 12/16/2024] [Indexed: 01/11/2025] Open
Abstract
The tumor secretome comprises the totality of protein factors secreted by various cell components within the tumor microenvironment, serving as the primary medium for signal transduction between tumor cells and between tumor cells and stromal cells. The deletion or mutation of the p53 gene leads to alterations in cellular secretion characteristics, contributing to the construction of the tumor microenvironment in a cell non-autonomous manner. This review discusses the critical roles of mutant p53 in regulating the tumor secretome to remodel the tumor microenvironment, drive tumor progression, and influence the plasticity of cancer-associated fibroblasts (CAFs) as well as the dynamics of tumor immunity by focusing on both secreted protein expression and secretion pathways. The aim is to provide new insights for targeted cancer therapies.
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Affiliation(s)
| | | | - Xiaoming Wu
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Chenggong Campus, 727 South Jingming Road, Kunming 650500, China; (L.Q.); (Z.M.)
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3
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Lou S, Lv H, Zhang L. Identification of Vesicle-Mediated Transport-Related Genes for Predicting Prognosis, Immunotherapy Response, and Drug Screening in Cervical Cancer. Immun Inflamm Dis 2024; 12:e70052. [PMID: 39513664 PMCID: PMC11544644 DOI: 10.1002/iid3.70052] [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: 08/01/2024] [Revised: 09/27/2024] [Accepted: 10/13/2024] [Indexed: 11/15/2024] Open
Abstract
BACKGROUND Cervical cancer is one of the most common malignancies among women. Vesicle-mediated transport mechanisms significantly influence tumor cell behavior through intercellular material exchange. However, prognostic significance in CC patients remains underexplored. RESEARCH DESIGN AND METHODS We identified differentially expressed vesicle-mediated transport-related genes from TCGA and GeneCards datasets through differential expression analysis. We constructed a prognostic model using Cox regression and LASSO regression, categorized patients into high- and low-risk groups, and validated the model in the GEO data set. A nomogram integrating clinical features and risk scores demonstrated the model's independent prognostic capability. We analyzed tumor immune cell infiltration, immune checkpoints, and predicted immunotherapy responses in the high- and low-risk groups. Finally, we screened potential drugs for targeting CC and conducted drug-sensitivity analysis. RESULTS We successfully established a 10-gene prognostic model based on VMTRGs. The low-risk group exhibited favorable prognosis, significant immune cell infiltration, and promising immunotherapy response, whereas the high-risk group showed higher sensitivity to chemotherapeutic agents such as Docetaxel and Paclitaxel. Potential drugs identified for targeting CC patients included Megestrol acetate, Lenvatinib, Adavosertib, and Barasertib. CONCLUSIONS The VMTRG-based prognostic model demonstrates reliable clinical prognostic value and enhances understanding of vesicle-mediated transport mechanisms in CC.
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Affiliation(s)
- Shuai Lou
- Department of Gynecology, Affiliated Jinhua HospitalZhejiang University School of MedicineJinhuaZhejiangChina
- Department of GynecologyJinhua Maternal and Child Health HospitalJinhuaZhejiangChina
| | - Hongqing Lv
- Department of Gynecology, Affiliated Jinhua HospitalZhejiang University School of MedicineJinhuaZhejiangChina
| | - Lin Zhang
- Department of Gynecology, Affiliated Jinhua HospitalZhejiang University School of MedicineJinhuaZhejiangChina
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Ozaki K, Nagahara H, Kawamura A, Ohgita T, Higashi S, Ogura K, Tsutsuki H, Iyoda S, Yokotani A, Yamaji T, Moss J, Yahiro K. Extracellular Vesicle Inhibitors Enhance Cholix-Induced Cell Death via Regulation of the JNK-Dependent Pathway. Toxins (Basel) 2024; 16:380. [PMID: 39330838 PMCID: PMC11435833 DOI: 10.3390/toxins16090380] [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: 08/02/2024] [Revised: 08/25/2024] [Accepted: 08/27/2024] [Indexed: 09/28/2024] Open
Abstract
Vibrio cholerae is an important foodborne pathogen. Cholix cytotoxin (Cholix), produced by V. cholerae, is a novel eukaryotic elongation factor 2 (eEF2) adenosine diphosphate ribosyltransferase that causes host cell death by inhibiting protein synthesis. However, the role of Cholix in the infectious diseases caused by V. cholerae remains unclear. Some bacterial cytotoxins are carried by host extracellular vesicles (EVs) and transferred to other cells. In this study, we investigated the effects of EV inhibitors and EV-regulating proteins on Cholix-induced hepatocyte death. We observed that Cholix-induced cell death was significantly enhanced in the presence of EV inhibitors (e.g., dimethyl amiloride, and desipramine) and Rab27a-knockdown cells, but it did not involve a sphingomyelin-dependent pathway. RNA sequencing analysis revealed that desipramine, imipramine, and EV inhibitors promoted the Cholix-activated c-Jun NH2-terminal kinase (JNK) pathway. Furthermore, JNK inhibition decreased desipramine-enhanced Cholix-induced poly (ADP-ribose) polymerase (PARP) cleavage. In addition, suppression of Apaf-1 by small interfering RNA further enhanced Cholix-induced PARP cleavage by desipramine. We identified a novel function of desipramine in which the stimulated JNK pathway promoted a mitochondria-independent cell death pathway by Cholix.
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Affiliation(s)
- Kazuya Ozaki
- Laboratory of Microbiology and Infection Control, Division of Biological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan; (K.O.); (H.N.); (A.K.); (S.H.); (A.Y.)
| | - Hiyo Nagahara
- Laboratory of Microbiology and Infection Control, Division of Biological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan; (K.O.); (H.N.); (A.K.); (S.H.); (A.Y.)
| | - Asaka Kawamura
- Laboratory of Microbiology and Infection Control, Division of Biological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan; (K.O.); (H.N.); (A.K.); (S.H.); (A.Y.)
| | - Takashi Ohgita
- Center for Instrumental Analysis, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan;
| | - Sachika Higashi
- Laboratory of Microbiology and Infection Control, Division of Biological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan; (K.O.); (H.N.); (A.K.); (S.H.); (A.Y.)
| | - Kohei Ogura
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8501, Japan;
| | - Hiroyasu Tsutsuki
- Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
| | - Sunao Iyoda
- Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo 162-8640, Japan;
| | - Atsushi Yokotani
- Laboratory of Microbiology and Infection Control, Division of Biological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan; (K.O.); (H.N.); (A.K.); (S.H.); (A.Y.)
- Kyoto Biken Laboratories, Inc., Kyoto 611-0041, Japan
| | - Toshiyuki Yamaji
- Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan;
- Department of Microbiology and Immunology, Faculty of Pharmacy, Juntendo University, Chiba 279-0013, Japan
| | - Joel Moss
- Clinical Care Medicine and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20824-0105, USA;
| | - Kinnosuke Yahiro
- Laboratory of Microbiology and Infection Control, Division of Biological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan; (K.O.); (H.N.); (A.K.); (S.H.); (A.Y.)
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Zhou X, Hang S, Wang Q, Xu L, Wang P. Decoding the Role of O-GlcNAcylation in Hepatocellular Carcinoma. Biomolecules 2024; 14:908. [PMID: 39199296 PMCID: PMC11353135 DOI: 10.3390/biom14080908] [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: 06/25/2024] [Revised: 07/16/2024] [Accepted: 07/22/2024] [Indexed: 09/01/2024] Open
Abstract
Post-translational modifications (PTMs) influence protein functionality by modulating protein stability, localization, and interactions with other molecules, thereby controlling various cellular processes. Common PTMs include phosphorylation, acetylation, ubiquitination, glycosylation, SUMOylation, methylation, sulfation, and nitrosylation. Among these modifications, O-GlcNAcylation has been shown to play a critical role in cancer development and progression, especially in hepatocellular carcinoma (HCC). This review outlines the role of O-GlcNAcylation in the development and progression of HCC. Moreover, we delve into the underlying mechanisms of O-GlcNAcylation in HCC and highlight compounds that target O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) to improve treatment outcomes. Understanding the role of O-GlcNAcylation in HCC will offer insights into potential therapeutic strategies targeting OGT and OGA, which could improve treatment for patients with HCC.
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Affiliation(s)
- Xinyu Zhou
- Department of Surgery, Zhejiang Chinese Medical University, Hangzhou 310053, China; (X.Z.); (S.H.)
| | - Sirui Hang
- Department of Surgery, Zhejiang Chinese Medical University, Hangzhou 310053, China; (X.Z.); (S.H.)
| | - Qingqing Wang
- Department of Hepatobiliary Surgery, The First Hospital of Jiaxing, Jiaxing 314051, China;
| | - Liu Xu
- Department of Hepatobiliary Surgery, The First Hospital of Jiaxing, Jiaxing 314051, China;
| | - Peter Wang
- Department of Medicine, Zhejiang Zhongwei Medical Research Center, Hangzhou 310000, China
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Sun S, Zhang Y, Li Y, Wei L. Crosstalk between colorectal cancer cells and cancer-associated fibroblasts in the tumor microenvironment mediated by exosomal noncoding RNAs. Front Immunol 2023; 14:1161628. [PMID: 37234178 PMCID: PMC10206140 DOI: 10.3389/fimmu.2023.1161628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 05/02/2023] [Indexed: 05/27/2023] Open
Abstract
Colorectal cancer (CRC) is a common malignant tumor of the digestive system, and its morbidity rates are increasing worldwide. Cancer-associated fibroblasts (CAFs), as part of the tumor microenvironment (TME), are not only closely linked to normal fibroblasts, but also can secrete a variety of substances (including exosomes) to participate in the regulation of the TME. Exosomes can play a key role in intercellular communication by delivering intracellular signaling substances (e.g., proteins, nucleic acids, non-coding RNAs), and an increasing number of studies have shown that non-coding RNAs of exosomal origin from CAFs are not only closely associated with the formation of the CRC microenvironment, but also increase the ability of CRC to grow in metastasis, mediate tumor immunosuppression, and are involved in the mechanism of drug resistance in CRC patients receiving. It is also involved in the mechanism of drug resistance after radiotherapy in CRC patients. In this paper, we review the current status and progress of research on CAFs-derived exosomal non-coding RNAs in CRC.
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Affiliation(s)
| | | | | | - Linlin Wei
- Department of Radiotherapy, Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Shenyang, Liaoning, China
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Exosomes in Colorectal Cancer: From Physiology to Clinical Applications. Int J Mol Sci 2023; 24:ijms24054382. [PMID: 36901813 PMCID: PMC10002401 DOI: 10.3390/ijms24054382] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/19/2023] [Accepted: 02/20/2023] [Indexed: 02/25/2023] Open
Abstract
Exosomes are nanosized vesicles that have been found to be involved in many diseases. Exosomes can mediate communication between cells in a variety of ways. Certain types of mediators derived from cancer cells can play a crucial role in the development of this pathology, promoting tumor growth, invasion, metastasis, angiogenesis, and immunomodulation. Exosomes in the bloodstream show promise as a future tool for detecting cancer at an early stage. The sensitivity and specificity of clinical exosome biomarkers need to be enhanced. Knowledge of exosomes is not only important for understanding the significance of cancer progression but also for providing clinicians with useful information for the diagnosis, treatment, and discovery of methods to prevent cancer from recurring. The widespread adoption of diagnostic tools based on exosomes may revolutionize cancer diagnosis and treatment. Tumor metastasis, chemoresistance, and immunity are all aided by exosomes. A potential new approach to cancer therapy involves preventing metastasis by inhibiting miRNA intracellular signaling and blocking the formation of pre-metastatic niches. For colorectal patients, exosomes represent a promising area of investigation for improving the diagnosis, treatment, and management. Reported data demonstrate that the serum expression level of certain exosomal miRNA is significantly higher in primary colorectal cancer patients. The present review discusses mechanisms and clinical implications of exosomes in colorectal cancer.
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Zhang Q, Wang C, Li R, Liu J, Wang J, Wang T, Wang B. The BAP31/miR-181a-5p/RECK axis promotes angiogenesis in colorectal cancer via fibroblast activation. Front Oncol 2023; 13:1056903. [PMID: 36895489 PMCID: PMC9989165 DOI: 10.3389/fonc.2023.1056903] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 02/03/2023] [Indexed: 02/25/2023] Open
Abstract
Background B-cell receptor-associated protein 31 (BAP31) has been recognized as a tumor-associated protein and has largely been shown to promote metastasis in a variety of cancers. Cancer metastasis arises through multistep pathways, and the induction of angiogenesis is shown to be a rate-limiting step in the process of tumor metastasis. Methods and results This study explored the effect of BAP31 on colorectal cancer (CRC) angiogenesis by regulating the tumor microenvironment. First, exosomes from BAP31-regulated CRCs affected the transition of normal fibroblasts to proangiogenic cancer-associated fibroblasts (CAFs) in vivo and in vitro. Next, microRNA sequencing was performed to analyze the microRNA expression profile of exosomes secreted from BAP31- overexpressing CRCs. The results indicated that the expression of BAP31 in CRCs significantly altered the levels of exosomal microRNAs, such as miR-181a- 5p. Meanwhile, an in vitro tube formation assay showed that fibroblasts with high levels of miR-181a-5p significantly promoted endothelial cell angiogenesis. Critically, we first identified that miR-181a-5p directly targeted the 3'-untranslated region (3'UTR) of reversion-inducing cysteine-rich protein with kazal motifs (RECK) using the dual-luciferase activity assay, which drove fibroblast transformation into proangiogenic CAFs by upregulating matrix metalloproteinase-9 (MMP-9) and phosphorylation of mothers against decapentaplegic homolog 2/Mothers against decapentaplegic homolog 3 (Smad2/3). Conclusion Exosomes from BAP31-overexpressing/BAP31-knockdown CRCs are found to manipulate the transition of fibroblasts into proangiogenic CAFs by the miR-181a-5p/RECK axis.
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Affiliation(s)
- Qi Zhang
- College of Life Science and Health, Northeastern University, Shenyang, Liaoning, China
| | - Changli Wang
- College of Life Science and Health, Northeastern University, Shenyang, Liaoning, China
| | - Ruijia Li
- College of Life Science and Health, Northeastern University, Shenyang, Liaoning, China
| | - Jingjing Liu
- College of Life Science and Health, Northeastern University, Shenyang, Liaoning, China
| | - Jiyu Wang
- College of Life Science and Health, Northeastern University, Shenyang, Liaoning, China
| | - Tianyi Wang
- College of Life Science and Health, Northeastern University, Shenyang, Liaoning, China
| | - Bing Wang
- College of Life Science and Health, Northeastern University, Shenyang, Liaoning, China
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Sattar RSA, Verma R, Nimisha, Kumar A, Dar GM, Apurva, Sharma AK, Kumari I, Ahmad E, Ali A, Mahajan B, Saluja SS. Diagnostic and prognostic biomarkers in colorectal cancer and the potential role of exosomes in drug delivery. Cell Signal 2022; 99:110413. [PMID: 35907519 DOI: 10.1016/j.cellsig.2022.110413] [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: 04/14/2022] [Revised: 07/13/2022] [Accepted: 07/15/2022] [Indexed: 11/03/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer with the second most frequent cause of death worldwide. One fourth to one fifth of the CRC cases are detected at advance stage. Early detection of colorectal cancer might help in decreasing mortality and morbidity worldwide. CRC being a heterogeneous disease, new non-invasive approaches are needed to complement and improve the screening and management of CRC. Reliable and early detectable biomarkers would improve diagnosis, prognosis, therapeutic responses, and will enable the prediction of drug response and recurrence risk. Over the past decades molecular research has demonstrated the potentials of CTCs, ctDNAs, circulating mRNAs, ncRNAs, and exosomes as tumor biomarkers. Non-invasive screening approaches using fecal samples for identification of altered gut microbes in CRC is also gaining attention. Exosomes can be potential candidates that can be employed in the drug delivery system. Further, the integration of in vitro, in vivo and in silico models that involve CRC biomarkers will help to understand the interactions occurring at the cellular level. This review summarizes recent update on CRC biomarkers and their application along with the nanoparticles followed by the application of organoid culture in CRC.
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Affiliation(s)
- Real Sumayya Abdul Sattar
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Renu Verma
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Nimisha
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Arun Kumar
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Ghulam Mehdi Dar
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Apurva
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Abhay Kumar Sharma
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Indu Kumari
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Ejaj Ahmad
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Asgar Ali
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Bhawna Mahajan
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Department of Biochemistry, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Sundeep Singh Saluja
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Department of GI Surgery, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India.
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Investigating Cancerous Exosomes’ Effects on CD8+ T-Cell IL-2 Production in a 3D Unidirectional Flow Bioreactor Using 3D Printed, RGD-Functionalized PLLA Scaffolds. J Funct Biomater 2022; 13:jfb13010030. [PMID: 35323230 PMCID: PMC8950614 DOI: 10.3390/jfb13010030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/07/2022] [Accepted: 03/08/2022] [Indexed: 11/16/2022] Open
Abstract
Exosomes from cancer cells are implicated in cancer progression and metastasis, carrying immunosuppressive factors that limit the antitumor abilities of immune cells. The development of a real-time, 3D cell/scaffold construct flow perfusion system has been explored as a novel tool in the study of T-cells and exosomes from cancer cells. Exosomes from human lung cancer (H1299 and A549) cells were co-cultured in a unidirectional flow bioreactor with CD8+ T-cells immobilized onto 3D-printed RGD-functionalized poly(L-lactic) acid (PLLA) scaffolds and assessed for IL-2 production. The IL-2 production was investigated for a wide range of T-cell to exosome ratios. With the successful incorporation of the RGD binding motif onto the PLLA surface at controllable densities, CD8+ T-cells were successfully attached onto 2D disks and 3D printed porous PLLA scaffolds. T-cell attachment increased with increasing RGD surface density. The diameter of the attached T-cells was 7.2 ± 0.2 µm for RGD densities below 0.5 nmoles/mm2 but dropped to 5.1 ± 0.3 µm when the RGD density was 2 nmoles/mm2 due to overcrowding. The higher the number of cancer exosomes, the less the IL-2 production by the surface-attached T-cells. In 2D disks, the IL-2 production was silenced for T-cell to exosome ratios higher than 1:10 in static conditions. IL-2 production silencing in static 3D porous scaffolds required ratios higher than 1:20. The incorporation of flow resulted in moderate to significant T-cell detachment. The portions of T-cells retained on the 3D scaffolds after exposure for 4 h to 0.15 or 1.5 mL/min of perfusion flow were 89 ± 11% and 30 ± 8%, respectively. On 3D scaffolds and in the presence of flow at 0.15 ml/min, both H1299 and A549 cancerous exosomes significantly suppressed IL-2 production for T-cell to exosome ratios of 1:1000. The much higher level of exosomes needed to silence the IL-2 production from T-cells cultured under unidirectional flow, compared to static conditions, denotes the importance of the culturing conditions and the hydrodynamic environment, on the interactions between CD8+ T-cells and cancer exosomes.
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Li Z, Wang T, Xin C, Song Y, Kong J, Xu J, Liu Q, Teng Y, Hou N, Cheng X, Yang G, Liu W, Zhou B, Zhang Y, Yang X, Wang J. Hgs Deficiency Caused Restrictive Cardiomyopathy via Disrupting Proteostasis. Int J Biol Sci 2022; 18:2018-2031. [PMID: 35342336 PMCID: PMC8935245 DOI: 10.7150/ijbs.69024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 02/06/2022] [Indexed: 12/24/2022] Open
Abstract
The molecular mechanisms underlying restrictive cardiomyopathy (RCM) are not fully understood. Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) is a vital element of Endosomal sorting required for transport (ESCRT), which mediates protein sorting for degradation and is crucial for protein homeostasis (proteostasis) maintenance. However, the physiological function and underlying mechanisms of HGS in RCM are unexplored. We hypothesized that HGS may play vital roles in cardiac homeostasis. Cardiomyocyte-specific Hgs gene knockout mice were generated and developed a phenotype similar to human RCM. Proteomic analysis revealed that Hgs deficiency impaired lysosomal homeostasis in cardiomyocytes. Loss of Hgs disrupted cholesterol transport and lysosomal integrity, resulting in lysosomal storage disorder (LSD) with aberrant autophagosome accumulation and protein aggregation. Suppression of protein aggregation by doxycycline treatment attenuated cardiac fibrosis, and diastolic dysfunction in Hgs-knockout mice. These findings uncovered a novel physiological role of HGS in regulating cardiac lysosomal homeostasis and proteostasis, suggesting that the deficient HGS contributes to LSD-associated RCM-like cardiomyopathy.
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Affiliation(s)
- Zhenhua Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China
| | - Tianle Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China
| | - Chong Xin
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China
| | - Yao Song
- Institute of Vascular Medicine, Peking University Third Hospital and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing 100191, China
| | - Jingyi Kong
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China
| | - Jingping Xu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China
| | - Qiqi Liu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China
| | - Yan Teng
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China
| | - Ning Hou
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China
| | - Xuan Cheng
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China
| | - Guan Yang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China
| | - Wenjia Liu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China
| | - Bin Zhou
- The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Youyi Zhang
- Institute of Vascular Medicine, Peking University Third Hospital and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing 100191, China.,✉ Corresponding authors: Jian Wang, PhD, State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China. Phone: +86 10 63895937, E-mail: . or Xiao Yang, State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China. Phone: +86 10 63895937, E-mail: . or Youyi Zhang, Institute of Vascular Medicine, Peking University Third Hospital, Beijing 100191, China. Phone: +86 10 82802306, E-mail:
| | - Xiao Yang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China.,✉ Corresponding authors: Jian Wang, PhD, State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China. Phone: +86 10 63895937, E-mail: . or Xiao Yang, State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China. Phone: +86 10 63895937, E-mail: . or Youyi Zhang, Institute of Vascular Medicine, Peking University Third Hospital, Beijing 100191, China. Phone: +86 10 82802306, E-mail:
| | - Jian Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China.,✉ Corresponding authors: Jian Wang, PhD, State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China. Phone: +86 10 63895937, E-mail: . or Xiao Yang, State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, China. Phone: +86 10 63895937, E-mail: . or Youyi Zhang, Institute of Vascular Medicine, Peking University Third Hospital, Beijing 100191, China. Phone: +86 10 82802306, E-mail:
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12
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Chang LC, Chiu HM, Wu MS, Shen TL. The Role of Small Extracellular Vesicles in the Progression of Colorectal Cancer and Its Clinical Applications. Int J Mol Sci 2022; 23:1379. [PMID: 35163305 PMCID: PMC8835972 DOI: 10.3390/ijms23031379] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 01/17/2022] [Accepted: 01/24/2022] [Indexed: 02/01/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide and a longstanding critical challenge for public health. Screening has been suggested to effectively reduce both the incidence and mortality of CRC. However, the drawback of the current screening modalities, both stool-based tests and colonoscopies, is limited screening adherence, which reduces the effectiveness of CRC screening. Blood tests are more acceptable than stool tests or colonoscopy as a first-line screening approach. Therefore, identifying blood biomarkers for detecting CRC and its precancerous neoplasms is urgently needed to fulfill the unmet clinical need. Currently, many kinds of blood contents, such as circulating tumor cells, circulating tumor nucleic acids, and extracellular vesicles, have been investigated as biomarkers for CRC detection. Among these, small extracellular vesicles (sEVs) have been demonstrated to detect CRC effectively in recent reports. sEVs enable intercellular shuttling-for instance, trafficking between recipient cancer cells and stromal cells-which can affect tumor initiation, proliferation, angiogenesis, immune regulation; metastasis, the cancer-specific molecules, such as proteins, microRNAs, long noncoding RNAs, and circular RNAs, loaded into cancer-derived sEVs may serve as biomarkers for the detection of cancers, including CRC. Indeed, accumulating evidence has shown that nucleic acids and proteins contained in CRC-derived sEVs are effective as blood biomarkers for CRC detection. However, investigations of the performance of sEVs for diagnosing CRC in clinical trials remains limited. Thus, the effectiveness of sEV biomarkers for diagnosing CRC needs further validation in clinical trials.
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Affiliation(s)
- Li-Chun Chang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan; (L.-C.C.); (H.-M.C.); (M.-S.W.)
- Health Management Center, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Han-Mo Chiu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan; (L.-C.C.); (H.-M.C.); (M.-S.W.)
- Health Management Center, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan; (L.-C.C.); (H.-M.C.); (M.-S.W.)
| | - Tang-Long Shen
- Department of Plant Pathology and Microbiology, National Taiwan University, Taipei 100, Taiwan
- Center for Biotechnology, National Taiwan University, Taipei 100, Taiwan
- Genome and Systems Biology Degree Program, National Taiwan University, Taipei 100, Taiwan
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13
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Ghafarkhani M, Avci CB, Rahbarghazi R, Karimi A, Sadeghizadeh M, Zarebkohan A, Bani F. Mild hyperthermia induced by gold nanorods acts as a dual-edge blade in the fate of SH-SY5Y cells via autophagy. Sci Rep 2021; 11:23984. [PMID: 34907215 PMCID: PMC8671444 DOI: 10.1038/s41598-021-02697-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 11/22/2021] [Indexed: 02/07/2023] Open
Abstract
Unraveling unwanted side effects of nanotechnology-based therapies like photothermal therapy (PTT) is vital in translational nanomedicine. Herein, we monitored the relationship between autophagic response at the transcriptional level by using a PCR array and tumor formation ability by colony formation assay in the human neuroblastoma cell line, SH-SY5Y, 48 h after being exposed to two different mild hyperthermia (43 and 48 °C) induced by PTT. In this regard, the promotion of apoptosis and autophagy were evaluated using immunofluorescence imaging and flow cytometry analyses. Protein levels of Ki-67, P62, and LC3 were measured using ELISA. Our results showed that of 86 genes associated with autophagy, the expression of 54 genes was changed in response to PTT. Also, we showed that chaperone-mediated autophagy (CMA) and macroautophagy are stimulated in PTT. Importantly, the results of this study also showed significant changes in genes related to the crosstalk between autophagy, dormancy, and metastatic activity of treated cells. Our findings illustrated that PTT enhances the aggressiveness of cancer cells at 43 °C, in contrast to 48 °C by the regulation of autophagy-dependent manner.
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Affiliation(s)
- Maryam Ghafarkhani
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, 516661-4733, Tabriz, Iran
| | - Cigir Biray Avci
- Department of Medical Biology, Medical Faculty, Ege University, Bornova, 35100, Izmir, Turkey
| | - Reza Rahbarghazi
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abbas Karimi
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Sadeghizadeh
- Department of Nanobiotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Amir Zarebkohan
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, 516661-4733, Tabriz, Iran.
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Farhad Bani
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, 516661-4733, Tabriz, Iran.
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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14
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Bioengineering of Extracellular Vesicles: Exosome-Based Next-Generation Therapeutic Strategy in Cancer. Bioengineering (Basel) 2021; 8:bioengineering8100139. [PMID: 34677212 PMCID: PMC8533396 DOI: 10.3390/bioengineering8100139] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 10/02/2021] [Accepted: 10/05/2021] [Indexed: 12/17/2022] Open
Abstract
Extracellular nano vesicles and exosomes hold compelling evidence in intercellular communication. Exosomal intracellular signal transduction is mediated by the transfer of cargo proteins, lipids, micro (mi)RNAs, long noncoding (lnc)RNAs, small interfering (si)RNAs, DNA, and other functional molecules that play a pivotal role in regulating tumor growth and metastasis. However, emerging research trends indicate that exosomes may be used as a promising tool in anticancer treatment. This review features a majority of the bioengineering applications of fabricated exosomal cargoes. It also encompasses how the manipulation and delivery of specific cargoes-noncoding RNAs (ncRNAs), recombinant proteins, immune-modulators, chemotherapeutic drugs, and other small molecules-may serve as a precise therapeutic approach in cancer management.
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15
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Chang YC, Chan MH, Li CH, Fang CY, Hsiao M, Chen CL. Exosomal Components and Modulators in Colorectal Cancer: Novel Diagnosis and Prognosis Biomarkers. Biomedicines 2021; 9:biomedicines9080931. [PMID: 34440135 PMCID: PMC8391321 DOI: 10.3390/biomedicines9080931] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 07/23/2021] [Accepted: 07/29/2021] [Indexed: 02/07/2023] Open
Abstract
The relatively high incidence and mortality rates for colorectal carcinoma (CRC) make it a formidable malignant tumor. Comprehensive strategies have been applied to predict patient survival and diagnosis. Various clinical regimens have also been developed to improve the therapeutic outcome. Extracellular vesicles (EVs) are recently proposed cellular structures that can be produced by natural or artificial methods and have been extensively studied. In addition to their innate functions, EVs can be manipulated to be drug carriers and exert many biological functions. The composition of EVs, their intravesicular components, and the surrounding tumor microenvironment are closely related to the development of colorectal cancer. Determining the expression profiles of exocytosis samples and using them as indicators for selecting effective combination therapy is an indispensable direction for EV study and should be regarded as a novel prediction platform in addition to cancer stage, prognosis, and other clinical assessments. In this review, we summarize the function, regulation, and application of EVs in the colon cancer research field. We provide an update on and discuss potential values for clinical applications of EVs. Moreover, we illustrate the specific markers, mediators, and genetic alterations of EVs in colorectal carcinogenesis. Furthermore, we outline the vital markers present in the EVs and discuss their plausible uses in colon cancer patient therapy in combination with the currently used clinical strategies. The development and application of these EVs will significantly improve the accuracy of diagnosis, lead to more precise prognoses, and may lead to the improved treatment of colorectal cancer.
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Affiliation(s)
- Yu-Chan Chang
- Department of Biomedical Imaging and Radiological Science, National Yang-Ming University, Taipei 112, Taiwan;
- Department of Biomedical Imaging and Radiological Science, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Ming-Hsien Chan
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan; (M.-H.C.); (C.-H.L.)
| | - Chien-Hsiu Li
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan; (M.-H.C.); (C.-H.L.)
| | - Chih-Yeu Fang
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli 350, Taiwan;
| | - Michael Hsiao
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan; (M.-H.C.); (C.-H.L.)
- Department of Biochemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Correspondence: (M.H.); (C.-L.C.); Tel.: +886-2-2787-1243 (M.H.); +886-2-2736-1661 (ext. 3139) (C.-L.C.); Fax: +886-2-2789-9931 (M.H.)
| | - Chi-Long Chen
- Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Department of Pathology, Taipei Medical University Hospital, Taipei 110, Taiwan
- Correspondence: (M.H.); (C.-L.C.); Tel.: +886-2-2787-1243 (M.H.); +886-2-2736-1661 (ext. 3139) (C.-L.C.); Fax: +886-2-2789-9931 (M.H.)
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16
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Heydari R, Abdollahpour-Alitappeh M, Shekari F, Meyfour A. Emerging Role of Extracellular Vesicles in Biomarking the Gastrointestinal Diseases. Expert Rev Mol Diagn 2021; 21:939-962. [PMID: 34308738 DOI: 10.1080/14737159.2021.1954909] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Extracellular vesicles (EVs) play an important role in cell-cell communication and regulation of various cellular functions under physiological and pathophysiological conditions through transferring their cargo to recipient cells. Molecular constituents of EVs are a fingerprinting profile of secreting cells which can be used as promising prognostic, diagnostic, and drug-response biomarkers in clinical settings. AREAS COVERED The present study provides a brief introduction about the biology of EVs and reviews methodologies used for EV isolation and characterization as well as high-throughput strategies to analyze EV contents. Furthermore, this review highlights the importance and unique role of EVs in the development and progression of gastrointestinal (GI) diseases, especially GI cancers, and then discusses their potential use, particularly those isolated from body fluids, in diagnosis and prognosis of GI diseases. EXPERT OPINION In-depth analysis of EV content can lead to the identification of new potential biomarkers for early diagnosis and prognosis prediction of GI diseases. The use of a more targeted approach by establishing more reproducible and standardized methods to decrease variations and obtain desired EV population as well as revisiting large pools of identified biomarkers and their evaluation in larger patient cohorts can result in the introduction of more reliable biomarkers in clinic.
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Affiliation(s)
- Raheleh Heydari
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Faezeh Shekari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Advanced Therapy Medicinal Product Technology Development Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Anna Meyfour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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17
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Identification of autophagy-related risk signatures for the prognosis, diagnosis, and targeted therapy in cervical cancer. Cancer Cell Int 2021; 21:362. [PMID: 34238288 PMCID: PMC8268251 DOI: 10.1186/s12935-021-02073-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 07/02/2021] [Indexed: 12/24/2022] Open
Abstract
Background To rummage autophagy-related prognostic, diagnostic, and therapeutic biomarkers in cervical cancer (CC). Methods The RNA-sequence and clinical information were from the TCGA and GTEx databases. We operated Cox regression to determine signatures related to overall survival (OS) and recurrence-free survival (RFS) respectively. The diagnostic and therapeutic effectiveness of prognostic biomarkers were further explored. Results We identified nine (VAMP7, MTMR14, ATG4D, KLHL24, TP73, NAMPT, CD46, HGS, ATG4C) and three risk signatures (SERPINA1, HSPB8, SUPT20H) with prognostic values for OS and RFS respectively. Six risk signatures (ATG4C, ATG4D, CD46, TP73, SERPINA1, HSPB8) were selected for qPCR. We screened five prognostic signatures(ATG4C, CD46, HSPB8, MTMR14, NAMPT) with diagnostic function through the GEO database. Correlation between our models and treatment targets certificated the prognostic score provided a reference for precision medicine. Conclusions We constructed OS and RFS prognostic models in CC. Autophagy-related risk signatures might serve as diagnostic and therapeutic biomarkers. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02073-w.
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Pavlakis E, Neumann M, Stiewe T. Extracellular Vesicles: Messengers of p53 in Tumor-Stroma Communication and Cancer Metastasis. Int J Mol Sci 2020; 21:ijms21249648. [PMID: 33348923 PMCID: PMC7766631 DOI: 10.3390/ijms21249648] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 12/12/2022] Open
Abstract
Tumor progression to a metastatic and ultimately lethal stage relies on a tumor-supporting microenvironment that is generated by reciprocal communication between tumor and stromal host cells. The tumor–stroma crosstalk is instructed by the genetic alterations of the tumor cells—the most frequent being mutations in the gene Tumor protein p53 (TP53) that are clinically correlated with metastasis, drug resistance and poor patient survival. The crucial mediators of tumor–stroma communication are tumor-derived extracellular vesicles (EVs), in particular exosomes, which operate both locally within the primary tumor and in distant organs, at pre-metastatic niches as the future sites of metastasis. Here, we review how wild-type and mutant p53 proteins control the secretion, size, and especially the RNA and protein cargo of tumor-derived EVs. We highlight how EVs extend the cell-autonomous tumor suppressive activity of wild-type p53 into the tumor microenvironment (TME), and how mutant p53 proteins switch EVs into oncogenic messengers that reprogram tumor–host communication within the entire organism so as to promote metastatic tumor cell dissemination.
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Affiliation(s)
- Evangelos Pavlakis
- Institute of Molecular Oncology, Philipps University, 35034 Marburg, Germany; (E.P.); (M.N.)
| | - Michelle Neumann
- Institute of Molecular Oncology, Philipps University, 35034 Marburg, Germany; (E.P.); (M.N.)
| | - Thorsten Stiewe
- Institute of Molecular Oncology, Philipps University, 35034 Marburg, Germany; (E.P.); (M.N.)
- Universities of Giessen and Marburg Lung Center (UGMLC), German Center of Lung Research (DZL), Philipps University, 35034 Marburg, Germany
- Correspondence:
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19
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Charest A. Experimental and Biological Insights from Proteomic Analyses of Extracellular Vesicle Cargos in Normalcy and Disease. ADVANCED BIOSYSTEMS 2020; 4:e2000069. [PMID: 32815324 PMCID: PMC8091982 DOI: 10.1002/adbi.202000069] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 06/19/2020] [Indexed: 12/11/2022]
Abstract
Extracellular vesicles (EVs) offer a vehicle for diagnostic and therapeutic utility. EVs carry bioactive cargo and an accrued interest in their characterization has emerged. Efforts at identifying EV-enriched protein or RNA led to a surprising realization that EVs are excessively heterogeneous in nature. This diversity is originally attributed to vesicle sizes but it is becoming evident that different classes of EVs vehiculate distinct molecular cargos. Therefore, one of the current challenges in EV research is their selective isolation in quantities sufficient for efficient downstream analyses. Many protocols have been developed; however, reproducibility between research groups can be difficult to reach and inter-studies analyses of data from different isolation protocols are unmanageable. Therefore, there is an unmet need to optimize and standardize methods and protocols for the isolation and purification of EVs. This review focuses on the diverse techniques and protocols used over the years to isolate and purify EVs with a special emphasis on their adequacy for proteomics applications. By combining recent advances in specific isolation methods that yield superior quality of EV preparations and mass spectrometry techniques, the field is now prepared for transformative advancements in establishing distinct categorization and cargo identification of subpopulations based on EV surface markers.
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20
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Liu J, Li H, Wei C, Ding J, Lu J, Pan G, Mao A. circFAT1(e2) Promotes Papillary Thyroid Cancer Proliferation, Migration, and Invasion via the miRNA-873/ZEB1 Axis. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2020; 2020:1459368. [PMID: 33133224 PMCID: PMC7593750 DOI: 10.1155/2020/1459368] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 09/14/2020] [Accepted: 09/17/2020] [Indexed: 12/21/2022]
Abstract
Circular RNAs (circRNAs) play an extremely important regulatory role in the occurrence and development of various malignant tumors including papillary thyroid cancer (PTC). circFAT1(e2) is a new type of circRNA derived from exon 2 of the FAT1 gene, which is distributed in the cytoplasm and nucleus of PTC cells. However, so far, the role of circFAT1(e2) in PTC is still unclear. In this study, circFAT1(e2) was found to be highly expressed in PTC cell lines and tissues. circFAT1(e2) knockdown suppressed PTC cell growth, migration, and invasion. Also, circFAT1(e2) acted as a sponge for potential microRNAs (miRNAs) to modulate cancer progression. A potential miRNA target was discovered to be miR-873 which was targeted by circFAT1(e2) in PTC. The dual-luciferase assay conducted later also confirmed that there was indeed a direct interaction between circFAT1(e2) and miR-873. This study also confirmed that circFAT1(e2) inhibited the miR-873 expression and thus promoted the ZEB1 expression, thus affecting the proliferation, metastasis, and invasion of PTC cells. In conclusion, the results of this study indicated that circFAT1(e2) played a carcinogenic role by targeting the miR-873/ZEB1 axis to promote PTC invasion and metastasis, which might become a potential novel target for therapy of PTC.
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Affiliation(s)
- Jiazhe Liu
- Minhang Hospital, Fudan University, 170 Xin-Song Road, Shanghai 201199, China
| | - Hongchang Li
- Minhang Hospital, Fudan University, 170 Xin-Song Road, Shanghai 201199, China
| | - Chuanchao Wei
- Minhang Hospital, Fudan University, 170 Xin-Song Road, Shanghai 201199, China
| | - Junbin Ding
- Minhang Hospital, Fudan University, 170 Xin-Song Road, Shanghai 201199, China
| | - Jingfeng Lu
- Minhang Hospital, Fudan University, 170 Xin-Song Road, Shanghai 201199, China
| | - Gaofeng Pan
- Minhang Hospital, Fudan University, 170 Xin-Song Road, Shanghai 201199, China
| | - Anwei Mao
- Minhang Hospital, Fudan University, 170 Xin-Song Road, Shanghai 201199, China
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21
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Paul D, Roy A, Nandy A, Datta B, Borar P, Pal SK, Senapati D, Rakshit T. Identification of Biomarker Hyaluronan on Colon Cancer Extracellular Vesicles Using Correlative AFM and Spectroscopy. J Phys Chem Lett 2020; 11:5569-5576. [PMID: 32573237 DOI: 10.1021/acs.jpclett.0c01018] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Extracellular vesicles (EVs), naturally occurring nanosized vesicles secreted from cells, are essential for intercellular communication. They carry unique biomolecules on the surface or interior that are of great interest as biomarkers for various pathological conditions such as cancer. In this work, we use high-resolution atomic force microscopy (AFM) and spectroscopy (AFS) techniques to demonstrate differences between EVs derived from colon cancer cells and colon epithelial cells at the single-vesicle level. We observe that EV populations are significantly increased in the cancer cell media compared to the normal cell EVs. We show that both EVs display an EV marker, CD9, while EVs derived from the cancer cells are slightly higher in density. Hyaluronan (HA) is a nonsulfated glycosaminoglycan linked to malignant tumor growth according to recent reports. Interestingly, at the single-vesicle level, colon cancer EVs exhibit significantly increased HA surface densities compared to the normal EVs. Spectroscopic measurements such as Fourier transform infrared (FT-IR), circular dichroism (CD), and Raman spectroscopy unequivocally support the AFM and AFS measurements. To our knowledge, it represents the first report of detecting HA-coated EVs as a potential colon cancer biomarker. Taken together, this sensitive approach will be useful in identifying biomarkers in the early stages of detection and evaluation of cancer.
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Affiliation(s)
- Debashish Paul
- Department of Chemical, Biological & Macromolecular Sciences, S. N. Bose National Centre for Basic Sciences, Block - JD, Sector - III, Salt Lake City, Kolkata 700106, India
| | - Anuradha Roy
- Chemical Sciences Division, Saha Institute of Nuclear Physics, HBNI, 1/AF Bidhannagar, Kolkata 700064, India
| | - Arpita Nandy
- Chemical Sciences Division, Saha Institute of Nuclear Physics, HBNI, 1/AF Bidhannagar, Kolkata 700064, India
| | - Brateen Datta
- Department of Chemical, Biological & Macromolecular Sciences, S. N. Bose National Centre for Basic Sciences, Block - JD, Sector - III, Salt Lake City, Kolkata 700106, India
| | - Prateeka Borar
- Department of Biophysics, Centenary Campus, Bose Institute, P-1/12 C.I.T. Scheme VII-M, Kolkata 700054, India
| | - Samir Kumar Pal
- Department of Chemical, Biological & Macromolecular Sciences, S. N. Bose National Centre for Basic Sciences, Block - JD, Sector - III, Salt Lake City, Kolkata 700106, India
| | - Dulal Senapati
- Chemical Sciences Division, Saha Institute of Nuclear Physics, HBNI, 1/AF Bidhannagar, Kolkata 700064, India
| | - Tatini Rakshit
- Department of Chemical, Biological & Macromolecular Sciences, S. N. Bose National Centre for Basic Sciences, Block - JD, Sector - III, Salt Lake City, Kolkata 700106, India
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Xu L, Gimple RC, Lau WB, Lau B, Fei F, Shen Q, Liao X, Li Y, Wang W, He Y, Feng M, Bu H, Wang W, Zhou S. THE PRESENT AND FUTURE OF THE MASS SPECTROMETRY-BASED INVESTIGATION OF THE EXOSOME LANDSCAPE. MASS SPECTROMETRY REVIEWS 2020; 39:745-762. [PMID: 32469100 DOI: 10.1002/mas.21635] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 02/03/2020] [Accepted: 02/05/2020] [Indexed: 02/05/2023]
Abstract
Exosomes are critical intercellular messengers released upon the fusion of multivesicular bodies with the cellular plasma membrane that deliver their cargo in the form of extracellular vesicles. Containing numerous nonrandomly packed functional proteins, lipids, and RNAs, exosomes are vital intercellular messengers that contribute to the physiologic processes of the healthy organism. During the post-genome era, exosome-oriented proteomics have garnered great interest. Since its establishment, mass spectrometry (MS) has been indispensable for the field of proteomics research and has advanced rapidly to interrogate biological samples at a higher resolution and sensitivity. Driven by new methodologies and more advanced instrumentation, MS-based approaches have revolutionized our understanding of protein biology. As the access to online proteomics database platforms has blossomed, experimental data processing occurs with more speed and accuracy. Here, we review recent advances in the technological progress of MS-based proteomics and several new detection strategies for MS-based proteomics research. We also summarize the use of integrated online databases for proteomics research in the era of big data. © 2020 John Wiley & Sons Ltd. Mass Spec Rev.
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Affiliation(s)
- Lian Xu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, People's Republic of China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Ryan C Gimple
- Department of Medicine, Division of Regenerative Medicine, University of California, San Diego, La Jolla, CA.,Department of Pathology, Case Western Reserve University, Cleveland, OH
| | - Wayne Bond Lau
- Department of Emergency Medicine, Thomas Jefferson University Hospital, Philadelphia, PA
| | - Bonnie Lau
- Department of Emergency Medicine, Kaiser Permanente Santa Clara Medical Center, Affiliate of Stanford University, Stanford, CA
| | - Fan Fei
- Department of Neurosurgery, Sichuan People's Hospital, Chengdu, Sichuan, People's Republic of China
| | - Qiuhong Shen
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, People's Republic of China.,School of Biological Sciences, Chengdu Medical College, Chengdu, Sichuan, People's Republic of China
| | - Xiaolin Liao
- Department of Neurosurgery, Sichuan People's Hospital, Chengdu, Sichuan, People's Republic of China
| | - Yichen Li
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong, People's Republic of China
| | - Wei Wang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Ying He
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Min Feng
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Hong Bu
- Laboratory of Pathology, Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Wei Wang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, People's Republic of China
| | - Shengtao Zhou
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, People's Republic of China
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23
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Xiao Y, Zhong J, Zhong B, Huang J, Jiang L, Jiang Y, Yuan J, Sun J, Dai L, Yang C, Li Z, Wang J, Zhong T. Exosomes as potential sources of biomarkers in colorectal cancer. Cancer Lett 2020; 476:13-22. [DOI: 10.1016/j.canlet.2020.01.033] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 12/15/2019] [Accepted: 01/24/2020] [Indexed: 02/06/2023]
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24
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Moballegh Nasery M, Abadi B, Poormoghadam D, Zarrabi A, Keyhanvar P, Khanbabaei H, Ashrafizadeh M, Mohammadinejad R, Tavakol S, Sethi G. Curcumin Delivery Mediated by Bio-Based Nanoparticles: A Review. Molecules 2020; 25:E689. [PMID: 32041140 PMCID: PMC7037405 DOI: 10.3390/molecules25030689] [Citation(s) in RCA: 150] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 01/29/2020] [Accepted: 02/02/2020] [Indexed: 02/07/2023] Open
Abstract
Todays, nano-pharmaceutics is emerging as an important field of science to develop and improve efficacy of different drugs. Although nutraceuticals are currently being utilized in the prevention and treatment of various chronic diseases such as cancers, a number of them have displayed issues associated with their solubility, bioavailability, and bio-degradability. In the present review, we focus on curcumin, an important and widely used polyphenol, with diverse pharmacological activities such as anti-inflammatory, anti-carcinogenic, anti-viral, etc. Notwithstanding, it also exhibits poor solubility and bioavailability that may compromise its clinical application to a great extent. Therefore, the manipulation and encapsulation of curcumin into a nanocarrier formulation can overcome these major drawbacks and potentially may lead to a far superior therapeutic efficacy. Among different types of nanocarriers, biological and biopolymer carriers have attracted a significant attention due to their pleiotropic features. Thus, in the present review, the potential protective and therapeutic applications of curcumin, as well as different types of bio-nanocarriers, which can be used to deliver curcumin effectively to the different target sites will be discussed.
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Affiliation(s)
- Mahshid Moballegh Nasery
- Student Research Committee, Kerman University of Medical Sciences, Kerman 7619813159, Iran; (M.M.N.); (B.A.)
- Department of Toxicology & Pharmacology, School of Pharmacy, Kerman University of Medical Sciences, Kerman 7616911319, Iran
- Nanomedicine Research Association (NRA), Universal Scientific Education and Research Network (USERN), Tehran 7616911319, Iran
| | - Banafshe Abadi
- Student Research Committee, Kerman University of Medical Sciences, Kerman 7619813159, Iran; (M.M.N.); (B.A.)
| | - Delaram Poormoghadam
- Department of Medical Nanotechnology, Faculty of Advanced Sciences & Technology, Pharmaceutical Sciences Branch, Islamic Azad University, (IAUPS), Tehran 1916893813, Iran;
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul 34956, Turkey;
| | - Peyman Keyhanvar
- Research Center for Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran;
- Department of Medical Nanotechnology, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran
| | - Hashem Khanbabaei
- Medical Physics Department, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran;
| | - Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz 5166616471, Iran;
| | - Reza Mohammadinejad
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman 7616911319, Iran
| | - Shima Tavakol
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran 1449614525, Iran
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
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25
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Ng KW, Attig J, Young GR, Ottina E, Papamichos SI, Kotsianidis I, Kassiotis G. Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist. eLife 2019; 8:e50256. [PMID: 31729316 PMCID: PMC6877088 DOI: 10.7554/elife.50256] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 11/13/2019] [Indexed: 12/27/2022] Open
Abstract
Immune regulation is a finely balanced process of positive and negative signals. PD-L1 and its receptor PD-1 are critical regulators of autoimmune, antiviral and antitumoural T cell responses. Although the function of its predominant membrane-bound form is well established, the source and biological activity of soluble PD-L1 (sPD-L1) remain incompletely understood. Here, we show that sPD-L1 in human healthy tissues and tumours is produced by exaptation of an intronic LINE-2A (L2A) endogenous retroelement in the CD274 gene, encoding PD-L1, which causes omission of the transmembrane domain and the regulatory sequence in the canonical 3' untranslated region. The alternatively spliced CD274-L2A transcript forms the major source of sPD-L1 and is highly conserved in hominids, but lost in mice and a few related species. Importantly, CD274-L2A-encoded sPD-L1 lacks measurable T cell inhibitory activity. Instead, it functions as a receptor antagonist, blocking the inhibitory activity of PD-L1 bound on cellular or exosomal membranes.
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Affiliation(s)
- Kevin W Ng
- Retroviral Immunology, The Francis Crick InstituteLondonUnited Kingdom
| | - Jan Attig
- Retroviral Immunology, The Francis Crick InstituteLondonUnited Kingdom
| | - George R Young
- Retrovirus-Host Interactions, The Francis Crick InstituteLondonUnited Kingdom
| | - Eleonora Ottina
- Retroviral Immunology, The Francis Crick InstituteLondonUnited Kingdom
| | - Spyros I Papamichos
- Department of HaematologyDemocritus University of Thrace Medical SchoolAlexandroupolisGreece
| | - Ioannis Kotsianidis
- Department of HaematologyDemocritus University of Thrace Medical SchoolAlexandroupolisGreece
| | - George Kassiotis
- Retroviral Immunology, The Francis Crick InstituteLondonUnited Kingdom
- Department of MedicineFaculty of Medicine, Imperial College LondonLondonUnited Kingdom
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26
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Hon KW, Ab-Mutalib NS, Abdullah NMA, Jamal R, Abu N. Extracellular Vesicle-derived circular RNAs confers chemoresistance in Colorectal cancer. Sci Rep 2019; 9:16497. [PMID: 31712601 PMCID: PMC6848089 DOI: 10.1038/s41598-019-53063-y] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Accepted: 10/25/2019] [Indexed: 02/07/2023] Open
Abstract
Chemo-resistance is associated with poor prognosis in colorectal cancer (CRC), with the absence of early biomarker. Exosomes are microvesicles released by body cells for intercellular communication. Circular RNAs (circRNAs) are non-coding RNAs with covalently closed loops and enriched in exosomes. Crosstalk between circRNAs in exosomes and chemo-resistance in CRC remains unknown. This research aims to identify exosomal circRNAs associated with FOLFOX-resistance in CRC. FOLFOX-resistant HCT116 CRC cells (HCT116-R) were generated from parental HCT116 cells (HCT116-P) using periodic drug induction. Exosomes were characterized using transmission electron microscopy (TEM), Zetasizer and Western blot. Our exosomes were translucent cup-shaped structures under TEM with differential expression of TSG101, CD9, and CD63. We performed circRNAs microarray using exosomal RNAs from HCT116-R and HCT116-P cells. We validated our microarray data using serum samples. We performed drug sensitivity assay and cell cycle analysis to characterize selected circRNA after siRNA-knockdown. Using fold change >2 and p < 0.05, we identified 105 significantly upregulated and 34 downregulated circRNAs in HCT116-R exosomes. Knockdown of circ_0000338 improved the chemo-resistance of CRC cells. We have proposed that circ_0000338 may have dual regulatory roles in chemo-resistant CRC. Exosomal circ_0000338 could be a potential biomarker for further validation in CRC.
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Affiliation(s)
- Kha Wai Hon
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nurul Syakima Ab-Mutalib
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nik Muhd Aslan Abdullah
- Department of Oncology and Radiotherapy, UKM Medical Center, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Rahman Jamal
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nadiah Abu
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
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27
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Chen L, Han Y, Li Y, Chen B, Bai X, Belguise K, Wang X, Chen Y, Yi B, Lu K. Hepatocyte-derived exosomal MiR-194 activates PMVECs and promotes angiogenesis in hepatopulmonary syndrome. Cell Death Dis 2019; 10:853. [PMID: 31700002 PMCID: PMC6838168 DOI: 10.1038/s41419-019-2087-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 09/27/2019] [Accepted: 10/21/2019] [Indexed: 12/18/2022]
Abstract
Hepatopulmonary syndrome (HPS) is a serious vascular complication in the setting of liver disease. Factors produced by the liver are essential to regulate pulmonary angiogenesis in the pathogenesis of HPS; however, the pathogenic mechanisms of pulmonary angiogenesis are not fully understood. We investigated the role of HPS rat serum exosomes (HEs) and sham-operated rat serum exosomes (SEs) in the regulation of angiogenesis. We found that HEs significantly enhance PMVEC proliferation, migration, and tube formation. We further identified miR-194 was the most notably increased miRNA in HEs compared to SEs. Once released, hepatocyte-derived exosomal miR-194 was internalized by PMVECs, leading to the promotion of PMVEC proliferation, migration, and tube formation through direct targeting of THBS1, STAT1, and LIF. Importantly, the pathogenic role of exosomal miR-194 in initiating angiogenesis was reversed by P53 inhibition, exosome secretion inhibition or miR-194 inhibition. Additionally, high levels of miR-194 were found in serum exosomes and were positively correlated with P(A-a)O2 in HPS patients and rats. Thus, our results highlight that the exosome/miR-194 axis plays a critical pathologic role in pulmonary angiogenesis, representing a new therapeutic target for HPS.
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Affiliation(s)
- Lin Chen
- Department of Anaesthesia, Southwest Hospital, The Third Military Medical University, Chongqing, China
| | - Yi Han
- Department of Anaesthesia, Southwest Hospital, The Third Military Medical University, Chongqing, China
| | - Yujie Li
- Department of Anaesthesia, Southwest Hospital, The Third Military Medical University, Chongqing, China
| | - Bing Chen
- Department of Anaesthesia, Southwest Hospital, The Third Military Medical University, Chongqing, China
| | - Xuehong Bai
- Department of Anaesthesia, Southwest Hospital, The Third Military Medical University, Chongqing, China
| | - Karine Belguise
- LBCMCP, ×tégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Xiaobo Wang
- LBCMCP, ×tégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Yang Chen
- Department of Anaesthesia, Southwest Hospital, The Third Military Medical University, Chongqing, China.
| | - Bin Yi
- Department of Anaesthesia, Southwest Hospital, The Third Military Medical University, Chongqing, China.
| | - Kaizhi Lu
- Department of Anaesthesia, Southwest Hospital, The Third Military Medical University, Chongqing, China.
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28
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Kim H, Kim DW, Cho JY. Exploring the key communicator role of exosomes in cancer microenvironment through proteomics. Proteome Sci 2019; 17:5. [PMID: 31686989 PMCID: PMC6820930 DOI: 10.1186/s12953-019-0154-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 10/15/2019] [Indexed: 12/25/2022] Open
Abstract
There have been many attempts to fully understand the mechanism of cancer behavior. Yet, how cancers develop and metastasize still remain elusive. Emerging concepts of cancer biology in recent years have focused on the communication of cancer with its microenvironment, since cancer cannot grow and live alone. Cancer needs to communicate with other cells for survival, and thus they secrete various messengers, including exosomes that contain many proteins, miRNAs, mRNAs, etc., for construction of the tumor microenvironment. Moreover, these intercellular communications between cancer and its microenvironment, including stromal cells or distant cells, can promote tumor growth, metastasis, and escape from immune surveillance. In this review, we summarized the role of proteins in the exosome as communicators between cancer and its microenvironment. Consequently, we present cancer specific exosome proteins and their unique roles in the interaction between cancer and its microenvironment. Clinically, these exosomes might provide useful biomarkers for cancer diagnosis and therapeutic tools for cancer treatment.
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Affiliation(s)
- HuiSu Kim
- 1Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Dong Wook Kim
- 1Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Je-Yoel Cho
- 1Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul, South Korea.,2Department of Biochemistry, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826 Korea
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29
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Tian X, Shen H, Li Z, Wang T, Wang S. Tumor-derived exosomes, myeloid-derived suppressor cells, and tumor microenvironment. J Hematol Oncol 2019; 12:84. [PMID: 31438991 PMCID: PMC6704713 DOI: 10.1186/s13045-019-0772-z] [Citation(s) in RCA: 187] [Impact Index Per Article: 31.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 08/14/2019] [Indexed: 12/13/2022] Open
Abstract
Plenty of immune cells infiltrate into the tumor microenvironment (TME) during tumor progression, in which myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells with immunosuppressive activity. Tumor cells and stromal cells facilitate the activation and expansion of MDSCs in TME via intercellular communication, and expanded MDSCs suppress anti-tumor immune responses through direct and indirect mechanisms. Currently, exosomes, which are a kind of extracellular vesicles (EVs) that can convey functional components, are demonstrated to participate in the local and distal intercellular communication between cells. Numerous studies have supposed that tumor-derived exosomes (TEXs), whose assembly and release can be modulated by TME, are capable of modulating the cell biology of MDSCs, including facilitating their activation, promoting the expansion, and enhancing the immunosuppressive function. Therefore, in this review, we mainly focus on the role of TEXs in the cell-cell communication between tumor cells and MDSCs, and discuss their clinical applications.
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Affiliation(s)
- Xinyu Tian
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Han Shen
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Zhiyang Li
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
| | - Tingting Wang
- Department of Laboratory Medicine, Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi Children's Hospital, Wuxi, China.
| | - Shengjun Wang
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China.
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China.
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30
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Schuldner M, Dörsam B, Shatnyeva O, Reiners KS, Kubarenko A, Hansen HP, Finkernagel F, Roth K, Theurich S, Nist A, Stiewe T, Paschen A, Knittel G, Reinhardt HC, Müller R, Hallek M, von Strandmann EP. Exosome-dependent immune surveillance at the metastatic niche requires BAG6 and CBP/p300-dependent acetylation of p53. Theranostics 2019; 9:6047-6062. [PMID: 31534536 PMCID: PMC6735508 DOI: 10.7150/thno.36378] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 07/15/2019] [Indexed: 01/08/2023] Open
Abstract
Extracellular vesicles released by tumor cells contribute to the reprogramming of the tumor microenvironment and interfere with hallmarks of cancer including metastasis. Notably, melanoma cell-derived EVs are able to establish a pre-metastatic niche in distant organs, or on the contrary, exert anti-tumor activity. However, molecular insights into how vesicles are selectively packaged with cargo defining their specific functions remain elusive. Methods: Here, we investigated the role of the chaperone Bcl2-associated anthogene 6 (BAG6, synonym Bat3) for the formation of pro- and anti-tumor EVs. EVs collected from wildtype cells and BAG6-deficient cells were characterized by mass spectrometry and RNAseq. Their tumorigenic potential was analyzed using the B-16V transplantation mouse melanoma model. Results: We demonstrate that EVs from B-16V cells inhibit lung metastasis associated with the mobilization of Ly6Clow patrolling monocytes. The formation of these anti-tumor-EVs was dependent on acetylation of p53 by the BAG6/CBP/p300-acetylase complex, followed by recruitment of components of the endosomal sorting complexes required for transport (ESCRT) via a P(S/T)AP double motif of BAG6. Genetic ablation of BAG6 and disruption of this pathway led to the release of a distinct EV subtype, which failed to suppress metastasis but recruited tumor-promoting neutrophils to the pre-metastatic niche. Conclusion: We conclude that the BAG6/CBP/p300-p53 axis is a key pathway directing EV cargo loading and thus a potential novel microenvironmental therapeutic target.
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31
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Patton MC, Zubair H, Khan MA, Singh S, Singh AP. Hypoxia alters the release and size distribution of extracellular vesicles in pancreatic cancer cells to support their adaptive survival. J Cell Biochem 2019; 121:828-839. [PMID: 31407387 DOI: 10.1002/jcb.29328] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 07/15/2019] [Indexed: 12/17/2022]
Abstract
Pancreatic tumors are highly desmoplastic and poorly-vascularized, and therefore must develop adaptive mechanisms to sustain their survival under hypoxic condition. Extracellular vesicles (EV) play vital roles in pancreatic tumor pathobiology by facilitating intercellular communication. Here we studied the effect of hypoxia on the release of EVs and examined their role in adaptive survival of pancreatic cancer (PC) cells. Hypoxia promoted the release of EV in PC cell lines, MiaPaCa and AsPC1, wherein former exhibited a far greater induction. Moreover, a time-dependent, measurable and significant increase was recorded for small EV (SEV) in both the cell lines with only minimal induction observed for medium (MEV) and large EVs (LEV). Similarly, noticeable changes in size distribution of SEV were also recorded with a shift toward smaller average size under extreme hypoxia. Thrombospondin (apoptotic bodies marker) was exclusively detected on LEVs, while Arf6 (microvesicles marker) was mostly present on MEV with some expression in LEV as well. However, CD9 and CD63 (exosome markers) were expressed in both SEV and MEVs with a decreased expression recorded under hypoxia. Among all subfractions, SEV was the most bioactive in promoting the survival of hypoxic PC cells and hypoxia-inducible factor-1α stabilization was involved in heightened EV release under hypoxia and for their potency to promote hypoxic cell survival. Altogether, our findings provide a novel mechanism for the adaptive hypoxic survival of PC cells and should serve as the basis for future investigations on broader functional implications of EV.
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Affiliation(s)
- Mary C Patton
- Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.,Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama
| | - Haseeb Zubair
- Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.,Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama
| | - Mohammad Aslam Khan
- Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.,Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama
| | - Seema Singh
- Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.,Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama.,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama
| | - Ajay P Singh
- Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.,Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama.,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama
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32
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Bandu R, Oh JW, Kim KP. Mass spectrometry-based proteome profiling of extracellular vesicles and their roles in cancer biology. Exp Mol Med 2019; 51:1-10. [PMID: 30872566 PMCID: PMC6418213 DOI: 10.1038/s12276-019-0218-2] [Citation(s) in RCA: 103] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 12/12/2018] [Indexed: 01/19/2023] Open
Abstract
Over the past three decades, extracellular vesicles (EVs) have arisen as important mediators of intercellular communication that are involved in the transmission of biological signals between cells to regulate various biological processes. EVs are largely responsible for intercellular communication through the delivery of bioactive molecules, such as proteins, messenger RNAs (mRNAs), microRNAs (miRNAs), DNAs, lipids, and metabolites. EVs released from cancer cells play a significant role in signal transduction between cancer cells and the surrounding cells, which contributes to the formation of tumors and metastasis in the tumor microenvironment. In addition, EVs released from cancer cells migrate to blood vessels and flow into various biological fluids, including blood and urine. EVs and EV-loaded functional cargoes, including proteins and miRNAs, found in these biological fluids are important biomarkers for cancer diagnosis. Therefore, EV proteomics greatly contributes to the understanding of carcinogenesis and tumor progression and is critical for the development of biomarkers for the early diagnosis of cancer. To explore the potential use of EVs as a gateway to understanding cancer biology and to develop cancer biomarkers, we discuss the mass spectrometric identification and characterization of EV proteins from different cancers. Information provided in this review may help in understanding recent progress regarding EV biology and the potential roles of EVs as new noninvasive biomarkers and therapeutic targets. Tumor cells release tiny membrane-encapsulated packages known as extracellular vesicles containing proteins which could serve as prognostic disease biomarkers or therapeutic targets. Kwang Pyo Kim and colleagues from Kyung Hee University in Yongin, South Korea, review the use of mass spectrometry to profile the diversity of proteins found in these tumor-derived packages. The proteins found in these vesicles help mediate communication between cancer cells and their surrounding tissues. Different tumor types share many of these proteins in common, but there are differences in the protein profile related to cancer-associated biological processes such as metastasis and cell proliferation. Tests based on the proteins contained in these vesicles could help clinicians better identify, diagnose and treat specific cancers, although large, multicenter studies are needed to validate such strategies.
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Affiliation(s)
- Raju Bandu
- Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin, Republic of Korea
| | - Jae Won Oh
- Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin, Republic of Korea
| | - Kwang Pyo Kim
- Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin, Republic of Korea. .,Department of Biomedical Science and Technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul, Republic of Korea.
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33
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Weston WW, Ganey T, Temple HT. The Relationship between Exosomes and Cancer: Implications for Diagnostics and Therapeutics. BioDrugs 2019; 33:137-158. [DOI: 10.1007/s40259-019-00338-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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34
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Jimenez L, Yu H, McKenzie AJ, Franklin JL, Patton JG, Liu Q, Weaver AM. Quantitative Proteomic Analysis of Small and Large Extracellular Vesicles (EVs) Reveals Enrichment of Adhesion Proteins in Small EVs. J Proteome Res 2019; 18:947-959. [PMID: 30608700 DOI: 10.1021/acs.jproteome.8b00647] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Extracellular vesicles (EVs) are important mediators of cell-cell communication due to their cargo content of proteins, lipids, and RNAs. We previously reported that small EVs (SEVs) called exosomes promote directed and random cell motility, invasion, and serum-independent growth. In contrast, larger EVs (LEVs) were not active in those assays, but might have unique functional properties. In order to identify protein cargos that may contribute to different functions of SEVs and LEVs, we used isobaric tags for relative and absolute quantitation (iTRAQ)-liquid chromatography (LC) tandem mass spectrometry (MS) on EVs isolated from a colon cancer cell line. Bioinformatics analyses revealed that SEVs are enriched in proteins associated with cell-cell junctions, cell-matrix adhesion, exosome biogenesis machinery, and various signaling pathways. In contrast, LEVs are enriched in proteins associated with ribosome and RNA biogenesis, processing, and metabolism. Western blot analysis of EVs purified from two different cancer cell types confirmed the enrichment of cell-matrix and cell-cell adhesion proteins in SEVs. Consistent with those data, we found that cells exhibit enhanced adhesion to surfaces coated with SEVs compared to an equal protein concentration of LEVs. These data suggest that a major function of SEVs is to promote cellular adhesion.
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Affiliation(s)
- Lizandra Jimenez
- Department of Cell and Developmental Biology , Vanderbilt University School of Medicine , Nashville , Tennessee 37232 , United States
| | - Hui Yu
- Department of Internal Medicine , University of New Mexico , Albuquerque , New Mexico 87131 , United States
| | - Andrew J McKenzie
- Sarah Cannon Research Institute , Nashville , Tennessee 37203 , United States
| | - Jeffrey L Franklin
- Department of Cell and Developmental Biology , Vanderbilt University School of Medicine , Nashville , Tennessee 37232 , United States.,Department of Medicine , Vanderbilt University Medical Center , Nashville , Tennessee 37212 , United States
| | - James G Patton
- Department of Biological Sciences , Vanderbilt University School of Medicine , Nashville , Tennessee 37212 , United States
| | - Qi Liu
- Department of Biostatistics , Vanderbilt University Medical Center , Nashville , Tennessee 37232 , United States
| | - Alissa M Weaver
- Department of Cell and Developmental Biology , Vanderbilt University School of Medicine , Nashville , Tennessee 37232 , United States.,Department of Pathology, Microbiology and Immunology , Vanderbilt University Medical Center , Nashville , Tennessee 37212 , United States
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35
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Choi D, Spinelli C, Montermini L, Rak J. Oncogenic Regulation of Extracellular Vesicle Proteome and Heterogeneity. Proteomics 2019; 19:e1800169. [PMID: 30561828 DOI: 10.1002/pmic.201800169] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Revised: 09/05/2018] [Indexed: 12/12/2022]
Abstract
Mutational and epigenetic driver events profoundly alter intercellular communication pathways in cancer. This effect includes deregulated release, molecular composition, and biological activity of extracellular vesicles (EVs), membranous cellular fragments ranging from a few microns to less than 100 nm in diameter and filled with bioactive molecular cargo (proteins, lipids, and nucleic acids). While EVs are usually classified on the basis of their physical properties and biogenetic mechanisms, recent analyses of their proteome suggest a larger than expected molecular diversity, a notion that is also supported by multicolour nano-flow cytometry and other emerging technology platforms designed to analyze single EVs. Both protein composition and EV diversity are markedly altered by oncogenic transformation, epithelial to mesenchymal transition, and differentiation of cancer stem cells. Interestingly, only a subset of EVs released from mutant cells may carry oncogenic proteins (e.g., EGFRvIII), hence, these EVs are often referred to as "oncosomes". Indeed, oncogenic transformation alters the repertoire of EV-associated proteins, increases the presence of pro-invasive cargo, and alters the composition of distinct EV populations. Molecular profiling of single EVs may reveal a more intricate effect of transforming events on the architecture of EV populations in cancer and shed new light on their biological role and diagnostic utility.
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Affiliation(s)
- Dongsic Choi
- Research Institute, Health Centre, Glen Site, McGill University, Montreal, Quebec, H4A 3J1, Canada
| | - Cristiana Spinelli
- Research Institute, Health Centre, Glen Site, McGill University, Montreal, Quebec, H4A 3J1, Canada
| | - Laura Montermini
- Research Institute, Health Centre, Glen Site, McGill University, Montreal, Quebec, H4A 3J1, Canada
| | - Janusz Rak
- Research Institute, Health Centre, Glen Site, McGill University, Montreal, Quebec, H4A 3J1, Canada
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36
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Zhang HL, Zhang AH, Miao JH, Sun H, Yan GL, Wu FF, Wang XJ. Targeting regulation of tryptophan metabolism for colorectal cancer therapy: a systematic review. RSC Adv 2019; 9:3072-3080. [PMID: 35518968 PMCID: PMC9060217 DOI: 10.1039/c8ra08520j] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 12/23/2018] [Indexed: 12/22/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most malignant cancers resulting from abnormal metabolism alterations. As one of the essential amino acids, tryptophan has a variety of physiological functions, closely related to regulation of immune system, central nervous system, gastrointestinal nervous system and intestinal microflora. Colorectal cancer, a type of high-grade malignancy disease, stems from a variety of factors and often accompanies inflammatory reactions, dysbacteriosis, and metabolic disorders. Colorectal cancer accompanies inflammation and imbalance of intestinal microbiota and affects tryptophan metabolism. It is known that metabolites, rate-limiting enzymes, and ARH in tryptophan metabolism are associated with the development of CRC. Specifically, IDO1 may be a potential therapeutic target in colorectal cancer treatment. Furthermore, the reduction of tryptophan amount is proportional to the poor quality of life for colorectal cancer patients. This paper aims to discuss the role of tryptophan metabolism in a normal organism and investigate the relationship between this amino acid and colorectal cancer. This study is expected to provide theoretical support for research related to targeted therapy for colorectal cancer. Furthermore, strategies that modify tryptophan metabolism, effectively inhibiting tumor progression, may be more effective for CRC treatment. Colorectal cancer (CRC) is one of the most malignant cancers resulting from abnormal metabolism alterations.![]()
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Affiliation(s)
- Hong-lian Zhang
- National Engineering Laboratory for the Development of Southwestern Endangered Medicinal Materials
- Guangxi Botanical Garden of Medicinal Plant
- Nanning
- China
- Sino-America Chinmedomics Technology Collaboration Center
| | - Ai-hua Zhang
- Sino-America Chinmedomics Technology Collaboration Center
- National TCM Key Laboratory of Serum Pharmacochemistry
- Chinmedomics Research Center of State Administration of TCM
- Laboratory of Metabolomics
- Department of Pharmaceutical Analysis
| | - Jian-hua Miao
- National Engineering Laboratory for the Development of Southwestern Endangered Medicinal Materials
- Guangxi Botanical Garden of Medicinal Plant
- Nanning
- China
| | - Hui Sun
- Sino-America Chinmedomics Technology Collaboration Center
- National TCM Key Laboratory of Serum Pharmacochemistry
- Chinmedomics Research Center of State Administration of TCM
- Laboratory of Metabolomics
- Department of Pharmaceutical Analysis
| | - Guang-li Yan
- Sino-America Chinmedomics Technology Collaboration Center
- National TCM Key Laboratory of Serum Pharmacochemistry
- Chinmedomics Research Center of State Administration of TCM
- Laboratory of Metabolomics
- Department of Pharmaceutical Analysis
| | - Fang-fang Wu
- National Engineering Laboratory for the Development of Southwestern Endangered Medicinal Materials
- Guangxi Botanical Garden of Medicinal Plant
- Nanning
- China
- Sino-America Chinmedomics Technology Collaboration Center
| | - Xi-jun Wang
- National Engineering Laboratory for the Development of Southwestern Endangered Medicinal Materials
- Guangxi Botanical Garden of Medicinal Plant
- Nanning
- China
- Sino-America Chinmedomics Technology Collaboration Center
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Ju Q, Zhao L, Gao J, Zhou L, Xu Y, Sun Y, Zhao X. Mutant p53 increases exosome-mediated transfer of miR-21-3p and miR-769-3p to promote pulmonary metastasis. Chin J Cancer Res 2019; 31:533-546. [PMID: 31354222 PMCID: PMC6613506 DOI: 10.21147/j.issn.1000-9604.2019.03.15] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Objective Tumor metastasis is a complex, multistep process that depends on tumor cells and their communication with the tumor microenvironment. A p53 gain-of-function mutant has been shown to enhance the tumorigenesis, invasion, and metastasis abilities of tumor cells. This study aimed to investigate the roles of p53 R273H mutation in the tumor microenvironment. Methods The in vitro and in vivo effects of the p53 R273H mutant on the invasion and metastasis of HCT116 cells were investigated. Exosomes from wild-type and HCT116-TP53(R273H) cells were cocultured with mouse embryonic fibroblasts (MEFs). The roles of differentially expressed exosomal microRNAs identified by microarray analysis were investigated. The functions of the p53 R273H mutant in tumor cells were also investigated via gene expression microarray and quantitative polymerase chain reaction (qPCR) analyses.
Results Introducing p53 R273H mutant into HCT116 cells significantly potentiated pulmonary metastasis in vivo. In the presence of exosomes derived from HCT116-TP53(R273H) cells, the exosomes were taken up by MEFs and became activated. Microarray analysis showed that the p53 R273H mutation increased the exosomal levels of miR-21-3p and miR-769-3p. Intriguingly, in clinical samples, miR-21-3p and miR-769-3p levels were significantly higher in patients with a p53 mutation than in those without this mutation. Furthermore, both miR-21-3p and miR-769-3p activated fibroblasts and exerted a synergistic effect via their target genes on the transforming growth factor-β (TGF-β)/Smad signaling pathway. The activated fibroblasts excreted cytokine TGF-β and may have reciprocally induced cancer cells to undergo epithelial-mesenchymal transition (EMT). Indeed, HCT116-TP53(R273H) cells showed increased expression of ZEB1 and SNAI2 and decreased transcription of several cell adhesion molecules.
Conclusions The mutant p53-exosomal miR-21-3p/miR-769-3p-fibroblast-cytokine circuit appears to be responsible for communication between tumor and stromal cells, with exosomal miRNAs acting as a bridge. miR-21-3p and miR-769-3p are potential predictive markers of pulmonary metastasis and candidate targets for therapeutic interventions.
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Affiliation(s)
- Qiang Ju
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Lina Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jiajia Gao
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Lanping Zhou
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yang Xu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yulin Sun
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xiaohang Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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38
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Zhang C, Ji Q, Yang Y, Li Q, Wang Z. Exosome: Function and Role in Cancer Metastasis and Drug Resistance. Technol Cancer Res Treat 2018; 17:1533033818763450. [PMID: 29681222 PMCID: PMC5949932 DOI: 10.1177/1533033818763450] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
As a kind of nanometric lipidic vesicles, exosomes have been presumed to play a leading role in the regulation of tumor microenvironment through exosomes-mediated transfer of proteins and genetic materials. Tumor-derived exosomes are recognized as a critical determinant of the tumor progression. Intriguingly, some current observations have identified that exosomes are essential for several intercellular exchanges of proteins, messenger RNAs, noncoding RNAs (including long noncoding RNAs and microRNAs) as well as to the process of cancer metastasis and drug resistance. Herein, we review the role of exosomes and their molecular cargos in cancer invasion and metastasis, summarize how they interact with antitumor agents, and highlight their translational implications.
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Affiliation(s)
- Chengcheng Zhang
- 1 Department of Medical Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,2 Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qing Ji
- 2 Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yue Yang
- 2 Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qi Li
- 2 Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhongqi Wang
- 1 Department of Medical Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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39
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Osti D, Del Bene M, Rappa G, Santos M, Matafora V, Richichi C, Faletti S, Beznoussenko GV, Mironov A, Bachi A, Fornasari L, Bongetta D, Gaetani P, DiMeco F, Lorico A, Pelicci G. Clinical Significance of Extracellular Vesicles in Plasma from Glioblastoma Patients. Clin Cancer Res 2018; 25:266-276. [PMID: 30287549 DOI: 10.1158/1078-0432.ccr-18-1941] [Citation(s) in RCA: 192] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 08/26/2018] [Accepted: 10/01/2018] [Indexed: 11/16/2022]
Abstract
PURPOSE Glioblastoma (GBM) is the most common primary brain tumor. The identification of blood biomarkers reflecting the tumor status represents a major unmet need for optimal clinical management of patients with GBM. Their high number in body fluids, their stability, and the presence of many tumor-associated proteins and RNAs make extracellular vesicles potentially optimal biomarkers. Here, we investigated the potential role of plasma extracellular vesicles from patients with GBM for diagnosis and follow-up after treatment and as a prognostic tool. EXPERIMENTAL DESIGN Plasma from healthy controls (n = 33), patients with GBM (n = 43), and patients with different central nervous system malignancies (n = 25) were collected. Extracellular vesicles were isolated by ultracentrifugation and characterized in terms of morphology by transmission electron microscopy, concentration, and size by nanoparticle tracking analysis, and protein composition by mass spectrometry. An orthotopic mouse model of human GBM confirmed human plasma extracellular vesicle quantifications. Associations between plasma extracellular vesicle concentration and clinicopathologic features of patients with GBM were analyzed. All statistical tests were two-sided. RESULTS GBM releases heterogeneous extracellular vesicles detectable in plasma. Plasma extracellular vesicle concentration was higher in GBM compared with healthy controls (P < 0.001), brain metastases (P < 0.001), and extra-axial brain tumors (P < 0.001). After surgery, a significant drop in plasma extracellular vesicle concentration was measured (P < 0.001). Plasma extracellular vesicle concentration was also increased in GBM-bearing mice (P < 0.001). Proteomic profiling revealed a GBM-distinctive signature. CONCLUSIONS Higher extracellular vesicle plasma levels may assist in GBM clinical diagnosis: their reduction after GBM resection, their rise at recurrence, and their protein cargo might provide indications about tumor, therapy response, and monitoring.
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Affiliation(s)
- Daniela Osti
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Massimiliano Del Bene
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.,Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Germana Rappa
- College of Medicine, Roseman University of Health Sciences, Las Vegas, Nevada
| | - Mark Santos
- College of Medicine, Roseman University of Health Sciences, Las Vegas, Nevada
| | | | - Cristina Richichi
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Stefania Faletti
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | | | | | - Angela Bachi
- IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy
| | - Lorenzo Fornasari
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Daniele Bongetta
- Neurosurgery Unit, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy.,Department of Clinical-Surgical, Diagnostic and Paediatric Sciences, Università degli Studi di Pavia, Pavia, Italy
| | - Paolo Gaetani
- Neurosurgery Unit, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy
| | - Francesco DiMeco
- Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.,Department of Neurological Surgery, Johns Hopkins Medical School, Baltimore, Maryland.,Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Aurelio Lorico
- College of Medicine, Roseman University of Health Sciences, Las Vegas, Nevada.,Mediterranean Institute of Oncology Foundation, Viagrande, Italy
| | - Giuliana Pelicci
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy. .,Department of Translational Medicine, Piemonte Orientale University "Amedeo Avogadro," Novara, Italy
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40
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Hayashi M, Kuroda K, Ihara K, Iwaya T, Isogai E. Suppressive effect of an analog of the antimicrobial peptide of LL‑37 on colon cancer cells via exosome‑encapsulated miRNAs. Int J Mol Med 2018; 42:3009-3016. [PMID: 30221678 PMCID: PMC6202099 DOI: 10.3892/ijmm.2018.3875] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 06/21/2018] [Indexed: 12/11/2022] Open
Abstract
Antimicrobial peptides (AMPs) are multifunctional factors with an important role in the innate immune system. Our previous studies revealed that the human cathelicidin LL-37 and its analog, FF/CAP18, limit the proliferation of colon cancer cell lines. In the present study, the exosomes released by HCT116 cells treated with FF/CAP18 were analyzed. After the treatment, exosomes were isolated from the culture supernatant by ultrafiltration and using the miRCURY™ Exosome Isolation Kit. Membrane vesicles 40-100-nm expressing CD63 and CD81 were identified before and after FF/CAP18 treatment. Exosome concentration in the culture supernatant was increased after treatment with FF/CAP18. Exosomes formed in HCT116 cells treated with FF/CAP18 induced growth suppression of the cells in a dose-dependent manner. By contrast, the exosomes formed in non-treated HCT116 cells did not affect cell viability. Microarray analysis of miRNA expression indicated that FF/CAP18 treatment induced increases in the expression of three miRNAs (miR-584-5p, miR-1202 and miR-3162-5p) in both HCT116 cells and exosomes. These results suggest that FF/CAP18 treatment increases exosome formation, and that exosome-encapsulated miRNAs suppress HCT116 cell proliferation. Exosomal miRNAs are considered to be involved in the dissemination of cell signals to control local cellular microenvironments. The present findings suggest that FF/CAP18 regulates cancer growth by modulating cell-to-cell communication. AMPs localize in the cytoplasm of cancer cells and enhance the expression of growth-suppressing miRNAs. These miRNAs are also transported to other cancer cells via exosomes. Therefore, transportation of these miRNAs has the potential to suppress cancer growth. AMPs exert their effects directly by targeting cancer cells and indirectly via exosomes.
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Affiliation(s)
- Miwa Hayashi
- Laboratory of Animal Microbiology, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi 980‑0845, Japan
| | - Kengo Kuroda
- Laboratory of Animal Microbiology, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi 980‑0845, Japan
| | - Kohei Ihara
- Laboratory of Animal Microbiology, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi 980‑0845, Japan
| | - Takahiro Iwaya
- Laboratory of Animal Microbiology, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi 980‑0845, Japan
| | - Emiko Isogai
- Laboratory of Animal Microbiology, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi 980‑0845, Japan
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41
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The multifaceted role of exosomes in cancer progression: diagnostic and therapeutic implications [corrected]. Cell Oncol (Dordr) 2018; 41:223-252. [PMID: 29667069 DOI: 10.1007/s13402-018-0378-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/20/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Recent advances in cancer biology have highlighted the relevance of exosomes and nanovesicles as carriers of genetic and biological messages between cancer cells and their immediate and/or distant environments. It has been found that these molecular cues may play significant roles in cancer progression and metastasis. Cancer cells secrete exosomes containing diverse molecules that can be transferred to recipient cells and/or vice versa to induce a plethora of biological processes, including angiogenesis, metastasis formation, therapeutic resistance, epithelial-mesenchymal transition and epigenetic/stemness (re)programming. While exosomes interact with cells within the tumour microenvironment to promote tumour growth, these vesicles can also facilitate the process of distant metastasis by mediating the formation of pre-metastatic niches. Next to their tumour promoting effects, exosomes have been found to serve as potential tools for cancer diagnosis and therapy. The ease of isolating exosomes and their content from different body fluids has led to the identification of diagnostic and prognostic biomarker signatures, as well as to predictive biomarker signatures for therapeutic responses. Exosomes can also be used as cargos to deliver therapeutic anti-cancer drugs, and they can be engineered to serve as vaccines for immunotherapy. Additionally, it has been found that inhibition of exosome secretion, and thus the transfer of oncogenic molecules, holds promise for inhibiting tumour growth. Here we provide recent information on the diverse roles of exosomes in various cellular and systemic processes governing cancer progression, and discuss novel strategies to halt this progression using exosome-based targeted therapies and methods to inhibit exosome secretion and the transfer of pro-tumorigenic molecules. CONCLUSIONS This review highlights the important role of exosomes in cancer progression and its implications for (non-invasive) diagnostics and the development of novel therapeutic strategies, as well as its current and future applications in clinical trials.
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42
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Nogués L, Benito-Martin A, Hergueta-Redondo M, Peinado H. The influence of tumour-derived extracellular vesicles on local and distal metastatic dissemination. Mol Aspects Med 2018; 60:15-26. [PMID: 29196097 PMCID: PMC5856602 DOI: 10.1016/j.mam.2017.11.012] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 11/18/2017] [Accepted: 11/27/2017] [Indexed: 02/07/2023]
Abstract
Extracellular vesicles (EVs) are key mediators of intercellular communication that have been ignored for decades. Tumour cells benefit from the secretion of vesicles as they can influence the behaviour of neighbouring tumour cells within the tumour microenvironment. Several studies have shown that extracellular vesicles play an active role in pre-metastatic niche formation and importantly, they are involved in the metastatic organotropism of different tumour types. Tumour-derived EVs carry and transfer molecules to recipient cells, modifying their behaviour through a process defined as "EV-driven education". EVs favour metastasis to sentinel lymph nodes and distal organs by reinforcing angiogenesis, inflammation and lymphangiogenesis. Hence, in this review we will summarize the main mechanisms by which tumour-derived EVs regulate lymph node and distal organ metastasis. Moreover, since some cancers metastasize through the lymphatic system, we will discuss recent discoveries about the presence and function of tumour EVs in the lymph. Finally, we will address the potential value of tumour EVs as prognostic biomarkers in liquid biopsies, specially blood and lymphatic fluid, and the use of these tools as early detectors of metastases.
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Affiliation(s)
- Laura Nogués
- Children's Cancer and Blood Foundation Laboratories, Department of Pediatrics, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10021, USA
| | - Alberto Benito-Martin
- Children's Cancer and Blood Foundation Laboratories, Department of Pediatrics, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10021, USA
| | - Marta Hergueta-Redondo
- Microenvironment and Metastasis Group, Department of Molecular Oncology, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain
| | - Héctor Peinado
- Children's Cancer and Blood Foundation Laboratories, Department of Pediatrics, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10021, USA; Microenvironment and Metastasis Group, Department of Molecular Oncology, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
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43
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Yan L, Dong X, Gao J, Liu F, Zhou L, Sun Y, Zhao X. A novel rapid quantitative method reveals stathmin-1 as a promising marker for esophageal squamous cell carcinoma. Cancer Med 2018; 7:1802-1813. [PMID: 29577639 PMCID: PMC5943482 DOI: 10.1002/cam4.1449] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 02/08/2018] [Accepted: 02/25/2018] [Indexed: 12/18/2022] Open
Abstract
Stathmin‐1 is a microtubule depolymerization protein that regulates cell division, growth, migration, and invasion. Overexpression of stathmin‐1 has been observed to be associated with metastasis, poor prognosis, and chemoresistance in various human cancers. Our previous studies found that serum stathmin‐1 was significantly elevated in patients with esophageal squamous cell carcinoma (ESCC) by ELISAs. Here, we constructed high‐affinity monoclonal antibodies and then developed a competitive AlphaLISA for rapid, accurate quantitation of stathmin‐1 in serum. Compared to ELISA, our homogeneous AlphaLISA showed better sensitivity and accuracy, a lower limit of detection, and a wider linear range. The measurements of nearly 1000 clinical samples showed that serum stathmin‐1 level increased dramatically in patients with squamous cell carcinoma (SCC), especially in ESCC, with a sensitivity and a specificity of 81% and 94%, respectively. Even for early stage ESCC, stathmin‐1 achieved an area under the receiver operating characteristic curve (AUC) of 0.88. Meanwhile, raised concentrations of stathmin‐1 were associated with lymph node metastasis and advanced cancer stage. Notably, various types of SCC showed significantly higher AUCs in serum stathmin‐1 detection compared to adenocarcinoma. Furthermore, we confirmed that stathmin‐1 was enriched in the oncogenic exosomes, which can explain the reason why it enters into the blood to serve as a tumor surrogate. In conclusion, this large‐scale and systematic study of serum stathmin‐1 measured by our newly established AlphaLISA showed that stathmin‐1 is a very promising diagnostic and predictive marker for SCC in the clinic, especially for ESCC.
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Affiliation(s)
- Lu Yan
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiu Dong
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jiajia Gao
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Fang Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Lanping Zhou
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yulin Sun
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiaohang Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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44
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Zhang HJ, Fang XH, Li J. Liquid biopsy in colorectal cancer. Shijie Huaren Xiaohua Zazhi 2018; 26:182-189. [DOI: 10.11569/wcjd.v26.i3.182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
In recent years, liquid biopsy technology, including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and exosomes, has been effectively used in the early diagnosis, relapse and drug resistance monitoring, and prognosis evaluation in colorectal cancer (CRC). In this paper, we review the basic research and clinical application of liquid biopsy in CRC.
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Affiliation(s)
- Hui-Juan Zhang
- Physical Examination Center, Zhengzhou Seventh People's Hospital, Zhengzhou 450003, He'nan Province, China
| | - Xin-Hui Fang
- Department of Gastroenterology, People's Hospital of Zhengzhou University, He'nan Provincial People's Hospital, Zhengzhou 450003, He'nan Province, China
| | - Jian Li
- Department of Gastroenterology, People's Hospital of Zhengzhou University, He'nan Provincial People's Hospital, Zhengzhou 450003, He'nan Province, China
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45
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Zhang S, Zhang Y, Qu J, Che X, Fan Y, Hou K, Guo T, Deng G, Song N, Li C, Wan X, Qu X, Liu Y. Exosomes promote cetuximab resistance via the PTEN/Akt pathway in colon cancer cells. ACTA ACUST UNITED AC 2017; 51:e6472. [PMID: 29160412 PMCID: PMC5685060 DOI: 10.1590/1414-431x20176472] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Accepted: 09/05/2017] [Indexed: 12/11/2022]
Abstract
Cetuximab is widely used in patients with metastatic colon cancer expressing wildtype KRAS. However, acquired drug resistance limits its clinical efficacy. Exosomes are nanosized vesicles secreted by various cell types. Tumor cell-derived exosomes participate in many biological processes, including tumor invasion, metastasis, and drug resistance. In this study, exosomes derived from cetuximab-resistant RKO colon cancer cells induced cetuximab resistance in cetuximab-sensitive Caco-2 cells. Meanwhile, exosomes from RKO and Caco-2 cells showed different levels of phosphatase and tensin homolog (PTEN) and phosphor-Akt. Furthermore, reduced PTEN and increased phosphorylated Akt levels were found in Caco-2 cells after exposure to RKO cell-derived exosomes. Moreover, an Akt inhibitor prevented RKO cell-derived exosome-induced drug resistance in Caco-2 cells. These findings provide novel evidence that exosomes derived from cetuximab-resistant cells could induce cetuximab resistance in cetuximab-sensitive cells, by downregulating PTEN and increasing phosphorylated Akt levels.
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Affiliation(s)
- S Zhang
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, China
| | - Y Zhang
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, China
| | - J Qu
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, China
| | - X Che
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, China
| | - Y Fan
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, China
| | - K Hou
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, China
| | - T Guo
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, China
| | - G Deng
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, China
| | - N Song
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, China
| | - C Li
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, China
| | - X Wan
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, China
| | - X Qu
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, China
| | - Y Liu
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, China
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46
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Marques D, Ferreira-Costa LR, Ferreira-Costa LL, Correa RDS, Borges AMP, Ito FR, Ramos CCDO, Bortolin RH, Luchessi AD, Ribeiro-dos-Santos Â, Santos S, Silbiger VN. Association of insertion-deletions polymorphisms with colorectal cancer risk and clinical features. World J Gastroenterol 2017; 23:6854-6867. [PMID: 29085228 PMCID: PMC5645618 DOI: 10.3748/wjg.v23.i37.6854] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 06/24/2017] [Accepted: 08/15/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the association between 16 insertion-deletions (INDEL) polymorphisms, colorectal cancer (CRC) risk and clinical features in an admixed population.
METHODS One hundred and forty patients with CRC and 140 cancer-free subjects were examined. Genomic DNA was extracted from peripheral blood samples. Polymorphisms and genomic ancestry distribution were assayed by Multiplex-PCR reaction, separated by capillary electrophoresis on the ABI 3130 Genetic Analyzer instrument and analyzed on GeneMapper ID v3.2. Clinicopathological data were obtained by consulting the patients’ clinical charts, intra-operative documentation, and pathology scoring.
RESULTS Logistic regression analysis showed that polymorphism variations in IL4 gene was associated with increased CRC risk, while TYMS and UCP2 genes were associated with decreased risk. Reference to anatomical localization of tumor Del allele of NFKB1 and CASP8 were associated with more colon related incidents than rectosigmoid. In relation to the INDEL association with tumor node metastasis (TNM) stage risk, the Ins alleles of ACE, HLAG and TP53 (6 bp INDEL) were associated with higher TNM stage. Furthermore, regarding INDEL association with relapse risk, the Ins alleles of ACE, HLAG, and UGT1A1 were associated with early relapse risk, as well as the Del allele of TYMS. Regarding INDEL association with death risk before 10 years, the Ins allele of SGSM3 and UGT1A1 were associated with death risk.
CONCLUSION The INDEL variations in ACE, UCP2, TYMS, IL4, NFKB1, CASP8, TP53, HLAG, UGT1A1, and SGSM3 were associated with CRC risk and clinical features in an admixed population. These data suggest that this cancer panel might be useful as a complementary tool for better clinical management, and more studies need to be conducted to confirm these findings.
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Affiliation(s)
- Diego Marques
- Laboratório de Bioanálise e Biotecnologia Molecular, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Programa de Pós-graduação em Ciências Farmacêutica, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belém 66055-080, Pará, Brazil
| | - Layse Raynara Ferreira-Costa
- Laboratório de Bioanálise e Biotecnologia Molecular, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
| | - Lorenna Larissa Ferreira-Costa
- Laboratório de Bioanálise e Biotecnologia Molecular, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
| | - Romualdo da Silva Correa
- Departamento de Cirurgia Oncológica, Liga Norte Riograndense Contra o Câncer, Natal 59040-000, Rio Grande do Norte, Brazil
| | - Aline Maciel Pinheiro Borges
- Departamento de Cirurgia Oncológica, Liga Norte Riograndense Contra o Câncer, Natal 59040-000, Rio Grande do Norte, Brazil
| | - Fernanda Ribeiro Ito
- Departamento de Cirurgia Oncológica, Liga Norte Riograndense Contra o Câncer, Natal 59040-000, Rio Grande do Norte, Brazil
| | - Carlos Cesar de Oliveira Ramos
- Laboratório de Patologia e Citopatologia, Liga Norte Riograndense Contra o Câncer, Natal 59040-000, Rio Grande do Norte, Brazil
| | - Raul Hernandes Bortolin
- Laboratório de Bioanálise e Biotecnologia Molecular, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Programa de Pós-graduação em Ciências Farmacêutica, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
| | - André Ducati Luchessi
- Laboratório de Bioanálise e Biotecnologia Molecular, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Programa de Pós-graduação em Ciências Farmacêutica, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
| | - Ândrea Ribeiro-dos-Santos
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belém 66055-080, Pará, Brazil
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém 66073-005, Pará, Brazil
| | - Sidney Santos
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belém 66055-080, Pará, Brazil
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém 66073-005, Pará, Brazil
| | - Vivian Nogueira Silbiger
- Laboratório de Bioanálise e Biotecnologia Molecular, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Programa de Pós-graduação em Ciências Farmacêutica, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
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Unconventional Secretion of Heat Shock Proteins in Cancer. Int J Mol Sci 2017; 18:ijms18050946. [PMID: 28468249 PMCID: PMC5454859 DOI: 10.3390/ijms18050946] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 04/25/2017] [Accepted: 04/27/2017] [Indexed: 12/17/2022] Open
Abstract
Heat shock proteins (HSPs) are abundant cellular proteins involved with protein homeostasis. They have both constitutive and inducible isoforms, whose expression levels are further increased by stress conditions, such as temperature elevation, reduced oxygen levels, infection, inflammation and exposure to toxic substances. In these situations, HSPs exert a pivotal role in offering protection, preventing cell death and promoting cell recovery. Although the majority of HSPs functions are exerted in the cytoplasm and organelles, several lines of evidence reveal that HSPs are able to induce cell responses in the extracellular milieu. HSPs do not possess secretion signal peptides, and their secretion was subject to widespread skepticism until the demonstration of the role of unconventional secretion forms such as exosomes. Secretion of HSPs may confer immune system modulation and be a cell-to-cell mediated form of increasing stress resistance. Thus, there is a wide potential for secreted HSPs in resistance of cancer therapy and in the development new therapeutic strategies.
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48
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Jia S, Zhang R, Li Z, Li J. Clinical and biological significance of circulating tumor cells, circulating tumor DNA, and exosomes as biomarkers in colorectal cancer. Oncotarget 2017; 8:55632-55645. [PMID: 28903450 PMCID: PMC5589689 DOI: 10.18632/oncotarget.17184] [Citation(s) in RCA: 109] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 03/28/2017] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer (CRC) has been the fourth leading cause of cancer-related mortality worldwide. Owing to clonal evolution and selection, CRC treatment needs multimodal therapeutic approaches and due monitoring of tumor progression and therapeutic efficacy. Liquid biopsy, involving the use of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and exosomes, may offer a promising noninvasive alternative for diagnosis and for real-time monitoring of tumor evolution and therapeutic response compared to traditional tissue biopsy. Monitoring of the disease processes can enable clinicians to readily adopt a strategy based on optimal therapeutic decision-making. This article provides an overview of the significant advances and the current clinical and biological significance of CTCs, ctDNA, and exosomes in CRC, as well as a comparison of the main merits and demerits of these three components. The hurdles that need to be resolved and potential directions to be followed with respect to liquid biopsies for detection and therapy of CRC are also discussed.
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Affiliation(s)
- Shiyu Jia
- Peking University Fifth School of Clinical Medicine, Beijing, People's Republic of China.,National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China.,Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China
| | - Rui Zhang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China.,Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China
| | - Ziyang Li
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China.,Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China.,Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Jinming Li
- Peking University Fifth School of Clinical Medicine, Beijing, People's Republic of China.,National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China.,Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China
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49
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Prattichizzo F, Micolucci L, Cricca M, De Carolis S, Mensà E, Ceriello A, Procopio AD, Bonafè M, Olivieri F. Exosome-based immunomodulation during aging: A nano-perspective on inflamm-aging. Mech Ageing Dev 2017; 168:44-53. [PMID: 28259747 DOI: 10.1016/j.mad.2017.02.008] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Revised: 01/23/2017] [Accepted: 02/25/2017] [Indexed: 12/19/2022]
Abstract
Exosomes are nanovesicles formed by inward budding of endosomal membranes. They exert complex immunomodulatory effects on target cells, acting both as antigen-presenting vesicles and as shuttles for packets of information such as proteins, coding and non-coding RNA, and nuclear and mitochondrial DNA fragments. Albeit different, all such functions seem to be encompassed in the adaptive mechanism mediating the complex interactions of the organism with a variety of stressors, providing both for defense and for the evolution of symbiotic relationships with others organisms (gut microbiota, bacteria, and viruses). Intriguingly, the newly deciphered human virome and exosome biogenesis seem to share some physical-chemical characteristics and molecular mechanisms. Exosomes are involved in immune system recognition of self from non-self throughout life: they are therefore ideal candidate to modulate inflamm-aging, the chronic, systemic, age-related pro-inflammatory status, which influence the development/progression of the most common age-related diseases (ARDs). Not surprisingly, recent evidence has documented exosomal alteration during aging and in association with ARDs, even though data in this field are still limited. Here, we review current knowledge on exosome-based trafficking between immune cells and self/non-self cells (i.e. the virome), sketching a nano-perspective on inflamm-aging and on the mechanisms involved in health maintenance throughout life.
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Affiliation(s)
- Francesco Prattichizzo
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and Centre of Biomedical Investigation on Diabetes and Associated Metabolic Disorders Network (CIBERDEM), 08036 Barcelona, Spain; Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy
| | - Luigina Micolucci
- Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy
| | - Monica Cricca
- Department of Experimental, Diagnostic, and Specialty Medicine, DIMES, University of Bologna, Bologna, Italy
| | - Sabrina De Carolis
- Department of Experimental, Diagnostic, and Specialty Medicine, DIMES, University of Bologna, Bologna, Italy
| | - Emanuela Mensà
- Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy
| | - Antonio Ceriello
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and Centre of Biomedical Investigation on Diabetes and Associated Metabolic Disorders Network (CIBERDEM), 08036 Barcelona, Spain; Department of Cardiovascular and Metabolic Diseases, IRCCS Multimedica, Sesto San Giovanni, Milan, Italy
| | - Antonio Domenico Procopio
- Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy; Center of Clinical Pathology and Innovative Therapy, National Institute INRCA-IRCCS, Ancona, Italy
| | - Massimiliano Bonafè
- Department of Experimental, Diagnostic, and Specialty Medicine, DIMES, University of Bologna, Bologna, Italy
| | - Fabiola Olivieri
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and Centre of Biomedical Investigation on Diabetes and Associated Metabolic Disorders Network (CIBERDEM), 08036 Barcelona, Spain; Center of Clinical Pathology and Innovative Therapy, National Institute INRCA-IRCCS, Ancona, Italy.
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50
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Zhang Y, Liu F, Yuan Y, Jin C, Chang C, Zhu Y, Zhang X, Tian C, He F, Wang J. Inflammasome-Derived Exosomes Activate NF-κB Signaling in Macrophages. J Proteome Res 2016; 16:170-178. [PMID: 27684284 DOI: 10.1021/acs.jproteome.6b00599] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Exosomes are secreted small vesicles that mediate various biological processes, such as tumorigenesis and immune response. However, whether the inflammasome signaling leads to the change of constituent of exosomes and its roles in immune response remains to be determined. We isolated the exosomes from macrophages with treatment of mock, endotoxin, or endotoxin/nigericin. A label-free quantification method by MS/MS was used to identify the components of exosomes. In total, 2331 proteins were identified and 513 proteins were exclusively detected in exosomes with endotoxin and nigericin treatment. The differentially expressed proteins were classified by Gene Ontology and KEGG pathways. The immune response-related proteins and signaling pathways were specifically enriched in inflammasome-derived exosomes. Moreover, we treated macrophages with the exosomes from different stimulation. We found that inflammasome-derived exosomes directly activate NF-κB signaling pathway, while the control or endotoxin-derived exosomes have no effect. The inflammatory signaling was amplified in neighbor cells in an exosome-dependent way. The inflammasome-derived exosomes might be used to augment the immune response in disease treatment, and preventing the transfer of these exosomes might ameliorate autoimmune diseases.
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Affiliation(s)
- Yuehui Zhang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine , Beijing 102206, China.,National Center for Protein Sciences Beijing , Beijing 102206, China
| | - Fangbing Liu
- Anhui Medical University , Hefei, Anhui 230032, China.,State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine , Beijing 102206, China.,National Center for Protein Sciences Beijing , Beijing 102206, China
| | - Yanzhi Yuan
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine , Beijing 102206, China.,National Center for Protein Sciences Beijing , Beijing 102206, China
| | - Chaozhi Jin
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine , Beijing 102206, China.,National Center for Protein Sciences Beijing , Beijing 102206, China
| | - Cheng Chang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine , Beijing 102206, China.,National Center for Protein Sciences Beijing , Beijing 102206, China
| | - Yunping Zhu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine , Beijing 102206, China.,National Center for Protein Sciences Beijing , Beijing 102206, China
| | - Xiuyuan Zhang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine , Beijing 102206, China.,National Center for Protein Sciences Beijing , Beijing 102206, China
| | - Chunyan Tian
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine , Beijing 102206, China.,National Center for Protein Sciences Beijing , Beijing 102206, China
| | - Fuchu He
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine , Beijing 102206, China.,National Center for Protein Sciences Beijing , Beijing 102206, China
| | - Jian Wang
- Anhui Medical University , Hefei, Anhui 230032, China.,State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine , Beijing 102206, China.,National Center for Protein Sciences Beijing , Beijing 102206, China
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