|
1
|
Zuo CJ, Tian J. Advancing the understanding of the role of apoptosis in lung cancer immunotherapy: Global research trends, key themes, and emerging frontiers. Hum Vaccin Immunother 2025; 21:2488074. [PMID: 40186454 PMCID: PMC11980473 DOI: 10.1080/21645515.2025.2488074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 03/12/2025] [Accepted: 03/30/2025] [Indexed: 04/07/2025] Open
Abstract
Apoptosis is vital for improving the efficacy of lung cancer (LC) immunotherapy by targeting cancer cell elimination. Despite its importance, there is a lack of comprehensive bibliometric studies analyzing global research on apoptosis in LC immunotherapy. This analysis aims to address this gap by highlighting key trends, contributors, and future directions. A total of 969 publications from 1996 to 2024 were extracted from the Web of Science Core Collection. Analysis was conducted using VOSviewer, CiteSpace, and the R package 'bibliometrix.' The study included contributions from 6,894 researchers across 1,469 institutions in 61 countries, with research published in 356 journals. The volume of publications has steadily increased, led by China and the United States, with Sichuan University as the top contributor. The journal Cancers published the most articles, while Cancer Research had the highest co-citations. Yu-Quan Wei was the leading author, and Jemal, A. was the most frequently co-cited. Key research themes include "cell death mechanisms," "immune regulation," "combination therapies," "gene and nanomedicine applications," and "traditional Chinese medicine (TCM)." Future research is likely to focus on "coordinated regulation of multiple cell death pathways," "modulation of the tumor immune microenvironment," "optimization of combination therapies," "novel strategies in gene regulation," and the "integration of TCM" for personalized treatment. This is the first bibliometric analysis on the role of apoptosis in LC immunotherapy, providing an landscape of global research patterns and emerging therapeutic strategies. The findings offer insights to guide future research and optimize treatment approaches.
Collapse
Affiliation(s)
- Chun-Jian Zuo
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jie Tian
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
2
|
Cho H, Ha SE, Singh R, Kim D, Ro S. microRNAs in Type 1 Diabetes: Roles, Pathological Mechanisms, and Therapeutic Potential. Int J Mol Sci 2025; 26:3301. [PMID: 40244147 PMCID: PMC11990060 DOI: 10.3390/ijms26073301] [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: 02/21/2025] [Revised: 03/26/2025] [Accepted: 03/28/2025] [Indexed: 04/18/2025] Open
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the progressive destruction of pancreatic β-cells, leading to insulin deficiency. The primary drivers of β-cell destruction in T1D involve autoimmune-mediated processes that trigger chronic inflammation and ultimately β-cell loss. Regulatory microRNAs (miRNAs) play a crucial role in modulating these processes by regulating gene expression through post-transcriptional suppression of target mRNAs. Dysregulated miRNAs have been implicated in T1D pathogenesis, serving as both potential diagnostic biomarkers and therapeutic targets. This review explores the role of miRNAs in T1D, highlighting their involvement in disease mechanisms across both rodent models and human patients. While current antidiabetic therapies manage T1D symptoms, they do not prevent β-cell destruction, leaving patients reliant on lifelong insulin therapy. By summarizing key miRNA expression profiles in diabetic animal models and patients, this review explores the potential of miRNA-based therapies to restore β-cell function and halt or slow the progression of the disease.
Collapse
Affiliation(s)
| | | | | | | | - Seungil Ro
- Department of Physiology & Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (H.C.); (S.E.H.); (R.S.); (D.K.)
| |
Collapse
|
|
3
|
Wu S, Li R, Jiang Y, Yu J, Zheng J, Li Z, Li M, Xin K, Wang Y, Xu Z, Li S, Chen X. Liquid biopsy in urothelial carcinoma: Detection techniques and clinical applications. Biomed Pharmacother 2023; 165:115027. [PMID: 37354812 DOI: 10.1016/j.biopha.2023.115027] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 06/26/2023] Open
Abstract
The types of urothelial carcinoma (UC) include urothelial bladder cancer and upper tract urothelial carcinoma. Current diagnostic techniques cannot meet the needs of patients. Liquid biopsy is an accurate method of determining the molecular profile of UC and is a cutting-edge and popular technique that is expected to complement existing detection techniques and benefit patients with UC. Circulating tumor cells, cell-free DNA, cell-free RNA, extracellular vesicles, proteins, and metabolites can be found in the blood, urine, or other bodily fluids and are examined during liquid biopsies. This article focuses on the components of liquid biopsies and their clinical applications in UC. Liquid biopsies have tremendous potential in multiple aspects of precision oncology, from early diagnosis and treatment monitoring to predicting prognoses. They may therefore play an important role in the management of UC and precision medicine.
Collapse
Affiliation(s)
- Siyu Wu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Rong Li
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Yuanhong Jiang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Jiazheng Yu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Jianyi Zheng
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Zeyu Li
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Mingyang Li
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Kerong Xin
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Yang Wang
- Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China.
| | - Zhenqun Xu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China.
| | - Shijie Li
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China.
| | - Xiaonan Chen
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China.
| |
Collapse
|
|
4
|
Molika P, Bissanum R, Surachat K, Pattanapanyasat K, Hanprasertpong J, Chotigeat W, Navakanitworakul R. Exploration of Extracellular Vesicle Long Non-Coding RNAs in Serum of Patients with Cervical Cancer. Oncology 2023; 102:53-66. [PMID: 37573780 DOI: 10.1159/000533145] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 06/28/2023] [Indexed: 08/15/2023]
Abstract
INTRODUCTION Cervical cancer (CC) is the fourth most common cancer type and a leading cause of cancer-related deaths in women worldwide. Its underlying molecular mechanisms are unclear. Cancer cell-derived extracellular vesicles (EVs) are involved in cancer development and progression by delivering regulatory factors, including microRNAs and long non-coding RNAs (lncRNAs). METHODS Here, we identified the EV lncRNA expression profiles associated with different developmental stages of CC using next-generation sequencing. EVs from the serum of patients with stages I-III CC and healthy donors were characterized using EV marker immunoblotting and transmission electron microscopy. RESULTS The EV concentration increases with progression of the disease. Most particles had a 100-250-nm diameter, and their sizes were similar in all groups. We identified many lncRNAs that were uniquely and differentially expressed (DE) in patients with different stages of CC. The pathway analysis results indicated that the upregulated DE EV lncRNAs abundant in stages I and II were associated with cell proliferation and inflammation and cancer progression pathways, respectively. LINC00941, LINC01910, LINC02454, and DSG2-AS1 were highly expressed, suggesting poor overall survival of CC patients. Interestingly, DSG2-AS1 was associated with the human papillomavirus infection pathway through AKT3, DLG1, and COL6A2 genes. CONCLUSION This is the first study that reports the levels of EVs and their lncRNA contents change during cancer development, demonstrating the existence of a unique vesicle-mediated cell-to-cell communication network underlying cancer progression.
Collapse
Affiliation(s)
- Piyatida Molika
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand,
| | - Rassanee Bissanum
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
- Translational Medicine Research Center, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
| | - Komwit Surachat
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
- Translational Medicine Research Center, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
| | - Kovit Pattanapanyasat
- Office for Research and Development, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Jitti Hanprasertpong
- Department of Research and Medical Innovation, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand
| | - Wilaiwan Chotigeat
- Department of Molecular Biotechnology and Bioinformatics, Faculty of Science, Prince of Songkla University, Hat Yai, Thailand
| | - Raphatphorn Navakanitworakul
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
| |
Collapse
|
|
5
|
Du Z, Zhang H, Feng Y, Zhan D, Li S, Tu C, Liu J, Wang J. Tumour-derived small extracellular vesicles contribute to the tumour progression through reshaping the systemic immune macroenvironment. Br J Cancer 2023; 128:1249-1266. [PMID: 36755063 PMCID: PMC10050072 DOI: 10.1038/s41416-023-02175-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 01/18/2023] [Accepted: 01/19/2023] [Indexed: 02/10/2023] Open
Abstract
BACKGROUND Tumour-derived small extracellular vesicles (sEVs) play a crucial role in cancer immunomodulation. In addition to tumour immune microenvironment, the peripheral immune system also contributes significantly to cancer progression and is essential for anticancer immunity. However, a comprehensive definition of which and how peripheral immune lineages are regulated by tumour-derived sEVs during cancer development remains incomplete. METHODS In this study, we used mass cytometry with extensive antibody panels to comprehensively construct the systemic immune landscape in response to tumour development and tumour-derived sEVs. RESULTS Systemic immunity was dramatically altered by tumour growth and tumour-derived sEVs. Tumour-derived sEVs significantly and extensively affected immune cell population composition as well as intracellular pathways, resulting in an immunosuppressive peripheral and tumour immune microenvironment, characterised by increased myeloid-derived suppressor cells and decreased Ly6C+CD8 T cells. These sEVs largely promoted hematopoietic recovery and accelerate the differentiation towards myeloid-derived suppressor cells. The knockdown of Rab27a reduced sEV secretion from tumour cells and delayed tumour growth and metastasis in vivo. CONCLUSIONS These results highlight that tumour-derived sEVs function as a bridge between peripheral immunity regulation and the tumour microenvironment, and contribute to cancer progression through altering the composition and function of the global immune macroenvironment.
Collapse
Affiliation(s)
- Zhimin Du
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 510095, Guangzhou, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China
- School of Nursing, Guangzhou Medical University, 510182, Guangzhou, China
| | - Hui Zhang
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 510095, Guangzhou, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China
| | - Yueyuan Feng
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 510095, Guangzhou, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China
| | - Dewen Zhan
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 510095, Guangzhou, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China
| | - Shuya Li
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 510095, Guangzhou, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China
| | - Chenggong Tu
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 510095, Guangzhou, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China
| | - Jinbao Liu
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 510095, Guangzhou, China.
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China.
| | - Jinheng Wang
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 510095, Guangzhou, China.
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China.
| |
Collapse
|
|
6
|
Kumar K, Kim E, Alhammadi M, Umapathi R, Aliya S, Tiwari JN, Park HS, Choi JH, Son CY, Vilian AE, Han YK, Bu J, Huh YS. Recent advances in microfluidic approaches for the isolation and detection of exosomes. Trends Analyt Chem 2023. [DOI: 10.1016/j.trac.2022.116912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
|
|
7
|
Xiong Y, Huang Q, Canady TD, Barya P, Liu S, Arogundade OH, Race CM, Che C, Wang X, Zhou L, Wang X, Kohli M, Smith AM, Cunningham BT. Photonic crystal enhanced fluorescence emission and blinking suppression for single quantum dot digital resolution biosensing. Nat Commun 2022; 13:4647. [PMID: 35941132 PMCID: PMC9360002 DOI: 10.1038/s41467-022-32387-w] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 07/29/2022] [Indexed: 12/21/2022] Open
Abstract
While nanoscale quantum emitters are effective tags for measuring biomolecular interactions, their utilities for applications that demand single-unit observations are limited by the requirements for large numerical aperture (NA) objectives, fluorescence intermittency, and poor photon collection efficiency resulted from omnidirectional emission. Here, we report a nearly 3000-fold signal enhancement achieved through multiplicative effects of enhanced excitation, highly directional extraction, quantum efficiency improvement, and blinking suppression through a photonic crystal (PC) surface. The approach achieves single quantum dot (QD) sensitivity with high signal-to-noise ratio, even when using a low-NA lens and an inexpensive optical setup. The blinking suppression capability of the PC improves the QDs on-time from 15% to 85% ameliorating signal intermittency. We developed an assay for cancer-associated miRNA biomarkers with single-molecule resolution, single-base mutation selectivity, and 10-attomolar detection limit. Additionally, we observed differential surface motion trajectories of QDs when their surface attachment stringency is altered by changing a single base in a cancer-specific miRNA sequence.
Collapse
Affiliation(s)
- Yanyu Xiong
- Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Holonyak Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Qinglan Huang
- Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Holonyak Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Taylor D Canady
- Holonyak Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Priyash Barya
- Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Holonyak Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Shengyan Liu
- Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Holonyak Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Opeyemi H Arogundade
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Caitlin M Race
- Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Holonyak Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Congnyu Che
- Holonyak Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Xiaojing Wang
- Holonyak Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Lifeng Zhou
- Holonyak Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Xing Wang
- Holonyak Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Manish Kohli
- Department of Oncology, Huntsman Cancer Institute, Salt Lake City, UT, 84112, USA
| | - Andrew M Smith
- Holonyak Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Carle Illinois College of Medicine, Urbana, IL, 61801, USA
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Cancer Center at Illinois, Urbana, IL, 61801, USA
| | - Brian T Cunningham
- Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
- Holonyak Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
- Cancer Center at Illinois, Urbana, IL, 61801, USA.
| |
Collapse
|
|
8
|
Mitchell MI, Ma J, Carter CL, Loudig O. Circulating Exosome Cargoes Contain Functionally Diverse Cancer Biomarkers: From Biogenesis and Function to Purification and Potential Translational Utility. Cancers (Basel) 2022; 14:3350. [PMID: 35884411 PMCID: PMC9318395 DOI: 10.3390/cancers14143350] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/01/2022] [Accepted: 07/07/2022] [Indexed: 12/12/2022] Open
Abstract
Although diagnostic and therapeutic treatments of cancer have tremendously improved over the past two decades, the indolent nature of its symptoms has made early detection challenging. Thus, inter-disciplinary (genomic, transcriptomic, proteomic, and lipidomic) research efforts have been focused on the non-invasive identification of unique "silver bullet" cancer biomarkers for the design of ultra-sensitive molecular diagnostic assays. Circulating tumor biomarkers, such as CTCs and ctDNAs, which are released by tumors in the circulation, have already demonstrated their clinical utility for the non-invasive detection of certain solid tumors. Considering that exosomes are actively produced by all cells, including tumor cells, and can be found in the circulation, they have been extensively assessed for their potential as a source of circulating cell-specific biomarkers. Exosomes are particularly appealing because they represent a stable and encapsulated reservoir of active biological compounds that may be useful for the non-invasive detection of cancer. T biogenesis of these extracellular vesicles is profoundly altered during carcinogenesis, but because they harbor unique or uniquely combined surface proteins, cancer biomarker studies have been focused on their purification from biofluids, for the analysis of their RNA, DNA, protein, and lipid cargoes. In this review, we evaluate the biogenesis of normal and cancer exosomes, provide extensive information on the state of the art, the current purification methods, and the technologies employed for genomic, transcriptomic, proteomic, and lipidomic evaluation of their cargoes. Our thorough examination of the literature highlights the current limitations and promising future of exosomes as a liquid biopsy for the identification of circulating tumor biomarkers.
Collapse
Affiliation(s)
- Megan I Mitchell
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA
| | - Junfeng Ma
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA
| | - Claire L Carter
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA
| | - Olivier Loudig
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA
| |
Collapse
|
|
9
|
Chen H, Zhao L, Meng Y, Qian X, Fan Y, Zhang Q, Wang C, Lin F, Chen B, Xu L, Huang W, Chen J, Wang X. Sulfonylurea receptor 1-expressing cancer cells induce cancer-associated fibroblasts to promote non-small cell lung cancer progression. Cancer Lett 2022; 536:215611. [PMID: 35240233 DOI: 10.1016/j.canlet.2022.215611] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 02/23/2022] [Accepted: 02/26/2022] [Indexed: 12/27/2022]
Abstract
Cancer-associated fibroblasts (CAFs) play a pivotal role in cancer progression; however, how CAFs are induced remains elusive. Sulfonylurea receptor 1 (SUR1) is a tumor-enhancer in non-small cell lung carcinoma (NSCLC). Here, we probed the influence of SUR1-expressing cancer cells on CAFs. Results showed that high SUR1 expression positively correlated with α-SMA positive staining of CAFs in tumor tissues and poor prognosis of NSCLC patients. SUR1 contributed to normal fibroblast (NF) transformation into CAFs and facilitated the growth and metastasis of NSCLC in vivo. Conditioned medium (CM) and exosomes from SUR1-expressing cancer cells induced CAFs and promoted fibroblast migration. In cancer cells, SUR1 promoted p70S6K-induced KH-type splicing regulatory protein (KHSRP) phosphorylation at S395 to inhibit the binding of KHSRP with let-7a precursor (pre-let-7a) and decreasing mature let-7a-5p expression in cancer cells and exosomes. Let-7a-5p delivered by exosomes blocked NF transformation into CAFs by targeting TGFBR1 to inactivate the TGF-β signaling pathway. Glibenclamide, which targets SUR1, restrained CAFs and suppressed tumor growth in patient-derived xenograft models. Furthermore, we found that let-7a-5p was decreased in the tissues and plasma exosomes of NSCLC patients. In summary, SUR1-expressing cancer cells induce NF transformation into CAFs in the tumor microenvironment and promote NSCLC progression by transferring less exosomal let-7a-5p. Glibenclamide is a promising anti-cancer drug, and plasma exosomal let-7a-5p level is a potential diagnostic biomarker for NSCLC patients. These findings provide new therapeutic strategies by targeting SUR1 in NSCLC.
Collapse
Affiliation(s)
- Hongling Chen
- Department of Pharmacology, Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Li Zhao
- Department of Pharmacology, Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Yuting Meng
- Department of Pharmacology, Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Xixi Qian
- Department of Pharmacology, Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Ya Fan
- Department of Pharmacology, Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Quanli Zhang
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China
| | - Chao Wang
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China
| | - Fan Lin
- Department of Cellular Biology, Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Baoan Chen
- Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Lin Xu
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China.
| | - Wenbin Huang
- Department of Pathology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, China.
| | - Jing Chen
- Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China.
| | - Xuerong Wang
- Department of Pharmacology, Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
| |
Collapse
|
|
10
|
Are cachexia-associated tumors transmitTERS of ER stress? Biochem Soc Trans 2021; 49:1841-1853. [PMID: 34338294 DOI: 10.1042/bst20210496] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 06/23/2021] [Accepted: 07/06/2021] [Indexed: 12/24/2022]
Abstract
Cancer cachexia is associated with deficient response to chemotherapy. On the other hand, the tumors of cachectic patients remarkably express more chemokines and have higher immune infiltration. For immunogenicity, a strong induction of the unfolded protein response (UPR) is necessary. UPR followed by cell surface exposure of calreticulin on the dying tumor cell is essential for its engulfment by macrophages and dendritic cells. However, some tumor cells upon endoplasmic reticulum (ER) stress can release factors that induce ER stress to other cells, in the so-called transmissible ER stress (TERS). The cells that received TERS produce more interleukin 6 (IL-6) and chemokines and acquire resistance to subsequent ER stress, nutrient deprivation, and genotoxic stress. Since ER stress enhances the release of extracellular vesicles (EVs), we suggest they can mediate TERS. It was found that ER stressed cachexia-inducing tumor cells transmit factors that trigger ER stress in other cells. Therefore, considering the role of EVs in cancer cachexia, the release of exosomes can possibly play a role in the process of blunting the immunogenicity of the cachexia-associated tumors. We propose that TERS can cause an inflammatory and immunosuppressive phenotype in cachexia-inducing tumors.
Collapse
|
|
11
|
Hur JY, Lee KY. Characteristics and Clinical Application of Extracellular Vesicle-Derived DNA. Cancers (Basel) 2021; 13:3827. [PMID: 34359729 PMCID: PMC8345206 DOI: 10.3390/cancers13153827] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/25/2021] [Accepted: 07/27/2021] [Indexed: 02/06/2023] Open
Abstract
Extracellular vesicles (EVs) carry RNA, proteins, lipids, and diverse biomolecules for intercellular communication. Recent studies have reported that EVs contain double-stranded DNA (dsDNA) and oncogenic mutant DNA. The advantage of EV-derived DNA (EV DNA) over cell-free DNA (cfDNA) is the stability achieved through the encapsulation in the lipid bilayer of EVs, which protects EV DNA from degradation by external factors. The existence of DNA and its stability make EVs a useful source of biomarkers. However, fundamental research on EV DNA remains limited, and many aspects of EV DNA are poorly understood. This review examines the known characteristics of EV DNA, biogenesis of DNA-containing EVs, methylation, and next-generation sequencing (NGS) analysis using EV DNA for biomarker detection. On the basis of this knowledge, this review explores how EV DNA can be incorporated into diagnosis and prognosis in clinical settings, as well as gene transfer of EV DNA and its therapeutic potential.
Collapse
Affiliation(s)
- Jae Young Hur
- Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul 05030, Korea;
- Department of Pathology, Konkuk University Medical Center, Seoul 05030, Korea
| | - Kye Young Lee
- Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul 05030, Korea;
- Department of Pulmonary Medicine, Konkuk University School of Medicine, Seoul 05030, Korea
| |
Collapse
|
|
12
|
Luchian T, Mereuta L, Park Y, Asandei A, Schiopu I. Single-molecule, hybridization-based strategies for short nucleic acids detection and recognition with nanopores. Proteomics 2021; 22:e2100046. [PMID: 34275186 DOI: 10.1002/pmic.202100046] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/21/2021] [Accepted: 07/13/2021] [Indexed: 12/23/2022]
Abstract
DNA nanotechnology has seen large developments over the last 30 years through the combination of detection and discovery of DNAs, and solid phase synthesis to increase the chemical functionalities on nucleic acids, leading to the emergence of novel and sophisticated in features, nucleic acids-based biopolymers. Arguably, nanopores developed for fast and direct detection of a large variety of molecules, are part of a revolutionary technological evolution which led to cheaper, smaller and considerably easier to use devices enabling DNA detection and sequencing at the single-molecule level. Through their versatility, the nanopore-based tools proved useful biomedicine, nanoscale chemistry, biology and physics, as well as other disciplines spanning materials science to ecology and anthropology. This mini-review discusses the progress of nanopore- and hybridization-based DNA detection, and explores a range of state-of-the-art applications afforded through the combination of certain synthetically-derived polymers mimicking nucleic acids and nanopores, for the single-molecule biophysics on short DNA structures.
Collapse
Affiliation(s)
- Tudor Luchian
- Department of Physics, Alexandru I. Cuza University, Iasi, Romania
| | - Loredana Mereuta
- Department of Physics, Alexandru I. Cuza University, Iasi, Romania
| | - Yoonkyung Park
- Department of Biomedical Science and Research Center for Proteinaceous Materials (RCPM), Chosun University, Gwangju, Republic of Korea
| | - Alina Asandei
- Interdisciplinary Research Institute, Sciences Department, "Alexandru I. Cuza" University, Iasi, Romania
| | - Irina Schiopu
- Interdisciplinary Research Institute, Sciences Department, "Alexandru I. Cuza" University, Iasi, Romania
| |
Collapse
|
|
13
|
Kinetics of plasma cfDNA predicts clinical response in non-small cell lung cancer patients. Sci Rep 2021; 11:7633. [PMID: 33828112 PMCID: PMC8027214 DOI: 10.1038/s41598-021-85797-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 02/19/2021] [Indexed: 02/06/2023] Open
Abstract
Tyrosine kinase inhibitors (TKIs), VEGF/VEGF receptor inhibitors (VEGFIs) and immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancers including non-small-cell lung cancer (NSCLC). This study aims to evaluate the utility of plasma cell-free DNA (cfDNA) as a prognostic biomarker and efficacy predictor of chemotherapy (CT) with or without these precision therapies in NSCLC patients. Peripheral cfDNA levels in 154 NSCLC patients were quantified before and after the first target cycle of chemotherapy. The correlations of cfDNA with tumor burden, clinical characteristics, progression-free survival (PFS)/disease-free survival (DFS), objective response ratio (ORR), and therapy regimens were analyzed respectively. Baseline cfDNA, but not post-chemotherapeutic cfDNA, positively correlates with tumor burden. Notably, cfDNA kinetics (cfDNA Ratio, the ratio of post-chemotherapeutic cfDNA to baseline cfDNA) well distinguished responsive individuals (CR/PR) from the non-responsive (PD/SD). Additionally, cfDNA Ratio was found negatively correlated with PFS in lung adenocarcinoma (LUAD), but not lung squamous-cell carcinoma (LUSC) which may be due to a limited number of LUSC patients in this cohort. LUAD patients with low cfDNA Ratio have prolonged PFS and improved ORR, compared to those with high cfDNA Ratio. When stratified by therapy regimen, the predictive value of cfDNA Ratio is significant in patients with chemotherapy plus VEGFIs, while more patients need be included to validate the value of cfDNA Ratio in other regimens. Thus, the kinetics of plasma cfDNA during chemotherapy may function as a prognostic biomarker and efficacy predictor for NSCLC patients.
Collapse
|
|
14
|
Xia J, Luo M, Dai L, Wang L, Wang L, Zhu J. Serum exosomal microRNAs as predictive markers for EGFR mutations in non-small-cell lung cancer. J Clin Lab Anal 2021; 35:e23743. [PMID: 33682961 PMCID: PMC8128312 DOI: 10.1002/jcla.23743] [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: 12/26/2020] [Revised: 02/10/2021] [Accepted: 02/10/2021] [Indexed: 12/18/2022] Open
Abstract
Background Current therapeutic drugs show positive effects on non–small‐cell lung cancer (NSCLC) patients with mutant epidermal growth factor receptor (EGFR) expression, whereas a lesser beneficial effect is generally noted on NSCLC patients with wild‐type EGFR. Therefore, identification of new detection methods for the accurate clinical diagnosis of NSCLC is essential. Methods In this study, tumor‐derived exosomes from the plasma of EGFR mutation and wild‐type NSCLC patients were isolated. Extensive exosomal miRNA profiling of EGFR mutation and wild‐type NSCLC patients, in comparison with healthy individuals, was performed using miRNA‐sequencing analysis. Results The variation of exosomal miRNA expression between control group (NR) and NCSLC samples (AM and AW) was identified. 96 significantly different expressed miRNAs were identified. Of these, 39 miRNAs were upregulated and 57 were downregulated. 11 miRNAs were downregulated, and 31 miRNAs were upregulated in the miRNA expression between NR and AM. Compared with healthy donors, 54 upregulated miRNAs and 36 downregulated miRNAs were observed in samples from AW patients. 40 different expressed miRNAs were identified in AM samples, compared with AW. Ten of upregulated miRNAs are miR‐260, miR‐1169, miR‐117, miR‐15b‐5p, miRNA‐731, miR‐342‐5p, miR‐ 898, miR‐1384, miR‐56, and miR‐1214. Ten of downregulated miRNAs are miR‐99b‐5p, miR‐1116, miR‐689, miR‐818, miR‐604, miR‐72, miR‐955, miR‐403, miR‐1228, and miR‐836. Conclusion The exosomal miR‐1169 and miR‐260 as potential candidates, which contain specific characteristics that can distinguish between wild‐type EGFR and mutant EGFR NSCLC patients in early‐stage cancers.
Collapse
Affiliation(s)
- Junbo Xia
- Department of Pulmonary Medicine, Affiliated Hangzhou First people's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Man Luo
- Department of Pulmonary Medicine, Affiliated Hangzhou First people's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lujun Dai
- Department of Pulmonary Medicine, Affiliated Hangzhou First people's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liusheng Wang
- Department of Pulmonary Medicine, Affiliated Hangzhou First people's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Limin Wang
- Department of Pulmonary Medicine, Affiliated Hangzhou First people's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jing Zhu
- Department of Infectious Diseases, Affiliated Hangzhou First people's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| |
Collapse
|
|
15
|
Qin B, Zhang Q, Hu XM, Mi TY, Yu HY, Liu SS, Zhang B, Tang M, Huang JF, Xiong K. How does temperature play a role in the storage of extracellular vesicles? J Cell Physiol 2020; 235:7663-7680. [PMID: 32324279 DOI: 10.1002/jcp.29700] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 03/31/2020] [Accepted: 03/31/2020] [Indexed: 02/06/2023]
Abstract
Extracellular vesicles (EVs) contain specific proteins, lipids, and nucleic acids that can be passed to other cells as signal molecules to alter their function. However, there are many problems and challenges in the conversion and clinical application of EVs. Storage and protection of EVs is one of the issues that need further research. To adapt to potential clinical applications, this type of problem must be solved. This review summarizes the storage practices of EVs in recent years, and explains the impact of temperature on the quality and stability of EVs during storage based on current research, and explains the potential mechanisms involved in this effect as much as possible.
Collapse
Affiliation(s)
- Bo Qin
- Department of Neurobiology and Human Anatomy, School of Basic Medical Science, Central South University, Changsha, Hunan, China
| | - Qi Zhang
- Department of Neurobiology and Human Anatomy, School of Basic Medical Science, Central South University, Changsha, Hunan, China
| | - Xi-Min Hu
- Clinical Medicine Eight-year Program, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Tuo-Yang Mi
- Department of Neurobiology and Human Anatomy, School of Basic Medical Science, Central South University, Changsha, Hunan, China
| | - Hai-Yang Yu
- Department of Neurobiology and Human Anatomy, School of Basic Medical Science, Central South University, Changsha, Hunan, China
| | - Shen-Shen Liu
- Department of Neurobiology and Human Anatomy, School of Basic Medical Science, Central South University, Changsha, Hunan, China
| | - Bin Zhang
- Department of Neurobiology and Human Anatomy, School of Basic Medical Science, Central South University, Changsha, Hunan, China
| | - Mu Tang
- Department of Neurobiology and Human Anatomy, School of Basic Medical Science, Central South University, Changsha, Hunan, China
| | - Ju-Fang Huang
- Department of Neurobiology and Human Anatomy, School of Basic Medical Science, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Ophthalmology, Changsha, Hunan, China
| | - Kun Xiong
- Department of Neurobiology and Human Anatomy, School of Basic Medical Science, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Ophthalmology, Changsha, Hunan, China
| |
Collapse
|
|
16
|
Shen M, Di K, He H, Xia Y, Xie H, Huang R, Liu C, Yang M, Zheng S, He N, Li Z. Progress in exosome associated tumor markers and their detection methods. MOLECULAR BIOMEDICINE 2020; 1:3. [PMID: 35006428 PMCID: PMC8603992 DOI: 10.1186/s43556-020-00002-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 07/15/2020] [Indexed: 02/08/2023] Open
Abstract
Exosomes are secreted by cells and are widely present in body fluids. Exosomes contain various molecular constituents of their cells of origin such as proteins, mRNA, miRNAs, DNA, lipid and glycans which are very similar as the content in tumor cells. These contents play an important role in various stages of tumor development, and make the tumor-derived exosome as a hot and emerging biomarker for various cancers diagnosis and management in non-invasive manner. The present problems of exosome isolation and detection hinder the application of exosomes. With the development of exosome isolation and detection technology, the contents of exosomes can be exploited for early cancer diagnosis. This review summarizes the recent progress on exosome-associated tumor biomarkers and some new technologies for exosome isolation and detection. Furthermore, we have also discussed the future development direction in exosome analysis methods.
Collapse
Affiliation(s)
- Mengjiao Shen
- Department of Clinical Laboratory, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
- Shanghai Health Development Research Center, Shanghai, China
| | - Kaili Di
- Department of Clinical Laboratory, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Hongzhang He
- Captis Diagnostics Inc, Pittsburgh, PA, 15213, USA
| | - Yanyan Xia
- Department of Clinical Laboratory, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Hui Xie
- Department of Clinical Laboratory, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Rongrong Huang
- Department of Clinical Laboratory, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Chang Liu
- Department of Clinical Laboratory, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Mo Yang
- Department of Biomedical Engineering, the Hong Kong Polytechnic University, Hunghom, Kowloon, Hong Kong, People's Republic of China.
| | - Siyang Zheng
- Department of Biomedical Engineering and Electrical & Computer Engineering, Carnegie Mellon University, 5000 Forbes Avenue, Scott Hall 4N211, Pittsburgh, PA, 15213, USA.
| | - Nongyue He
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China.
| | - Zhiyang Li
- Department of Clinical Laboratory, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China.
| |
Collapse
|
|
17
|
de Oliveira MC, Caires HR, Oliveira MJ, Fraga A, Vasconcelos MH, Ribeiro R. Urinary Biomarkers in Bladder Cancer: Where Do We Stand and Potential Role of Extracellular Vesicles. Cancers (Basel) 2020; 12:E1400. [PMID: 32485907 PMCID: PMC7352974 DOI: 10.3390/cancers12061400] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 05/23/2020] [Accepted: 05/28/2020] [Indexed: 12/24/2022] Open
Abstract
Extracellular vesicles (EVs) are small membrane vesicles released by all cells and involved in intercellular communication. Importantly, EVs cargo includes nucleic acids, lipids, and proteins constantly transferred between different cell types, contributing to autocrine and paracrine signaling. In recent years, they have been shown to play vital roles, not only in normal biological functions, but also in pathological conditions, such as cancer. In the multistep process of cancer progression, EVs act at different levels, from stimulation of neoplastic transformation, proliferation, promotion of angiogenesis, migration, invasion, and formation of metastatic niches in distant organs, to immune escape and therapy resistance. Moreover, as products of their parental cells, reflecting their genetic signatures and phenotypes, EVs hold great promise as diagnostic and prognostic biomarkers. Importantly, their potential to overcome the current limitations or the present diagnostic procedures has created interest in bladder cancer (BCa). Indeed, cystoscopy is an invasive and costly technique, whereas cytology has poor sensitivity for early staged and low-grade disease. Several urine-based biomarkers for BCa were found to overcome these limitations. Here, we review their potential advantages and downfalls. In addition, recent literature on the potential of EVs to improve BCa management was reviewed and discussed.
Collapse
Affiliation(s)
- Manuel Castanheira de Oliveira
- i3S—Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal; (H.R.C.); (M.J.O.); (A.F.); (M.H.V.)
- Tumor & Microenvironment Interactions Group, INEB - Institute of Biomedical Engineering, University of Porto, 4200-135 Porto, Portugal
- Department of Urology, Centro Hospitalar e Universitário do Porto, 4099-001 Porto, Portugal
- ICBAS-Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal
| | - Hugo R. Caires
- i3S—Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal; (H.R.C.); (M.J.O.); (A.F.); (M.H.V.)
- Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
| | - Maria J. Oliveira
- i3S—Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal; (H.R.C.); (M.J.O.); (A.F.); (M.H.V.)
- Tumor & Microenvironment Interactions Group, INEB - Institute of Biomedical Engineering, University of Porto, 4200-135 Porto, Portugal
- Department of Pathology, Faculty of Medicine, University of Porto, 4200-450 Porto, Portugal
| | - Avelino Fraga
- i3S—Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal; (H.R.C.); (M.J.O.); (A.F.); (M.H.V.)
- Tumor & Microenvironment Interactions Group, INEB - Institute of Biomedical Engineering, University of Porto, 4200-135 Porto, Portugal
- Department of Urology, Centro Hospitalar e Universitário do Porto, 4099-001 Porto, Portugal
- ICBAS-Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal
| | - M. Helena Vasconcelos
- i3S—Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal; (H.R.C.); (M.J.O.); (A.F.); (M.H.V.)
- Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Department of Biological Sciences, FFUP—Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
| | - Ricardo Ribeiro
- i3S—Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal; (H.R.C.); (M.J.O.); (A.F.); (M.H.V.)
- Tumor & Microenvironment Interactions Group, INEB - Institute of Biomedical Engineering, University of Porto, 4200-135 Porto, Portugal
- Laboratory of Genetics and Instituto de Saúde Ambiental, Faculdade de Medicina, University of Lisbon, 1649-028 Lisbon, Portugal
- Department of Clinical Pathology, Centro Hospitalar e Universitário de Coimbra, 3004-561 Coimbra, Portugal
| |
Collapse
|
|
18
|
Bandopadhyay M, Bharadwaj M. Exosomal miRNAs in hepatitis B virus related liver disease: a new hope for biomarker. Gut Pathog 2020; 12:23. [PMID: 32346400 PMCID: PMC7183117 DOI: 10.1186/s13099-020-00353-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 03/31/2020] [Indexed: 02/06/2023] Open
Abstract
The World Health Organisation, in its 2019 progress report on HIV, viral hepatitis and STDs indicates that 257 million people are afflicted with chronic HBV infections, of which, 1 million patients lose their lives every year due to HBV related chronic liver diseases including serious complications such as liver cirrhosis and hepatocellular carcinoma. The course of HBV infection and associated liver injury depend on several host factors, genetic variability of the virus, and the host viral interplay. The challenge of medical science is the early diagnosis/identification of the potential for development of fatal complications like liver cirrhosis and HCC so that timely medical intervention can improve the chances of survival. Currently, neither the vaccination regime nor the diagnostic methods are completely effective as reflected in the high number of annual deaths. It is evident from numerous publications that microRNAs (miRNAs) are the critical regulators of gene expression and various cellular processes like proliferation, development, differentiation, apoptosis and tumorigenesis. Expressions of these diminutive RNAs are significantly affected in cancerous tissues as a result of numerous genomic and epigenetic modifications. Exosomes are membrane-derived vesicles (30–100 nm) secreted by normal as well as malignant cells, and are present in all body fluids. They are recognized as critical molecules in intercellular communication between cells through horizontal transfer of information via their cargo, which includes selective proteins, mRNAs and miRNAs. Exosomal miRNAs are transferred to recipient cells where they can regulate target gene expression. This provides an insight into the elementary biology of cancer progression and therefore the development of therapeutic approaches. This concise review outlines various on-going research on miRNA mediated regulation of HBV pathogenesis with special emphasis on association of exosomal miRNA in advanced stage liver disease like hepatocellular carcinoma. This review also discusses the possible use of exosomal miRNAs as biomarkers in the early detection of HCC and liver cirrhosis.
Collapse
Affiliation(s)
- Manikankana Bandopadhyay
- Molecular Genetics and Biochemistry, National Institute of Cancer Prevention and Research (NICPR), Indian Council of Medical Research (ICMR), Noida, Uttar Pradesh 201301 India
| | - Mausumi Bharadwaj
- Molecular Genetics and Biochemistry, National Institute of Cancer Prevention and Research (NICPR), Indian Council of Medical Research (ICMR), Noida, Uttar Pradesh 201301 India
| |
Collapse
|
|
19
|
Kalani MYS, Alsop E, Meechoovet B, Beecroft T, Agrawal K, Whitsett TG, Huentelman MJ, Spetzler RF, Nakaji P, Kim S, Van Keuren-Jensen K. Extracellular microRNAs in blood differentiate between ischaemic and haemorrhagic stroke subtypes. J Extracell Vesicles 2020; 9:1713540. [PMID: 32128071 PMCID: PMC7034450 DOI: 10.1080/20013078.2020.1713540] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 12/19/2019] [Accepted: 12/23/2019] [Indexed: 02/07/2023] Open
Abstract
Rapid identification of patients suffering from cerebral ischaemia, while excluding intracerebral haemorrhage, can assist with patient triage and expand patient access to chemical and mechanical revascularization. We sought to identify blood-based, extracellular microRNAs 15 (ex-miRNAs) derived from extracellular vesicles associated with major stroke subtypes using clinical samples from subjects with spontaneous intraparenchymal haemorrhage (IPH), aneurysmal subarachnoid haemorrhage (SAH) and ischaemic stroke due to cerebral vessel occlusion. We collected blood from patients presenting with IPH (n = 19), SAH (n = 17) and ischaemic stroke (n = 21). We isolated extracellular vesicles from plasma, extracted RNA cargo, 20 sequenced the small RNAs and performed bioinformatic analyses to identify ex-miRNA biomarkers predictive of the stroke subtypes. Sixty-seven miRNAs were significantly variant across the stroke subtypes. A subset of exmiRNAs differed between haemorrhagic and ischaemic strokes, and LASSO analysis could distinguish SAH from the other subtypes with an accuracy of 0.972 ± 0.002. Further analyses predicted 25 miRNA classifiers that stratify IPH from ischaemic stroke with an accuracy of 0.811 ± 0.004 and distinguish haemorrhagic from ischaemic stroke with an accuracy of 0.813 ± 0.003. Blood-based, ex-miRNAs have predictive value, and could be capable of distinguishing between major stroke subtypes with refinement and validation. Such a biomarker could one day aid in the triage of patients to expand the pool eligible for effective treatment.
Collapse
Affiliation(s)
- M Yashar S Kalani
- Departments of Neurological Surgery and Neuroscience, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Eric Alsop
- Division of Neurogenomics, The Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Bessie Meechoovet
- Division of Neurogenomics, The Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Taylor Beecroft
- Division of Neurogenomics, The Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Komal Agrawal
- Division of Neurogenomics, The Translational Genomics Research Institute, Phoenix, AZ, USA
| | | | - Matthew J Huentelman
- Division of Neurogenomics, The Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Robert F Spetzler
- Department of Neurological Surgery, Barrow Neurological Institute, Phoenix, AZ, USA
| | - Peter Nakaji
- Department of Neurosurgery, Banner Heath and University of Arizona College of Medicine, Phoenix, AZ, USA
| | - Seungchan Kim
- Center for Computational Systems Biology, Department of Electrical and Computer Engineering, Roy G. Perry College of Engineering, Prairie View A & M University, Prairie View, TX, USA
| | | |
Collapse
|
|
20
|
Digital-resolution detection of microRNA with single-base selectivity by photonic resonator absorption microscopy. Proc Natl Acad Sci U S A 2019; 116:19362-19367. [PMID: 31501320 DOI: 10.1073/pnas.1904770116] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Circulating exosomal microRNA (miR) represents a new class of blood-based biomarkers for cancer liquid biopsy. The detection of miR at a very low concentration and with single-base discrimination without the need for sophisticated equipment, large volumes, or elaborate sample processing is a challenge. To address this, we present an approach that is highly specific for a target miR sequence and has the ability to provide "digital" resolution of individual target molecules with high signal-to-noise ratio. Gold nanoparticle tags are prepared with thermodynamically optimized nucleic acid toehold probes that, when binding to a target miR sequence, displace a probe-protecting oligonucleotide and reveal a capture sequence that is used to selectively pull down the target-probe-nanoparticle complex to a photonic crystal (PC) biosensor surface. By matching the surface plasmon-resonant wavelength of the nanoparticle tag to the resonant wavelength of the PC nanostructure, the reflected light intensity from the PC is dramatically and locally quenched by the presence of each individual nanoparticle, enabling a form of biosensor microscopy that we call Photonic Resonator Absorption Microscopy (PRAM). Dynamic PRAM imaging of nanoparticle tag capture enables direct 100-aM limit of detection and single-base mismatch selectivity in a 2-h kinetic discrimination assay. The PRAM assay demonstrates that ultrasensitivity (<1 pM) and high selectivity can be achieved on a direct readout diagnostic.
Collapse
|
|
21
|
Abstract
Bladder cancer (BC) is the second highest morbid malignancy of the urinary tract and the fifth most common cancer worldwide. BC is highly malignant with significant morbidity and mortality, especially muscle-invasive BC (MIBC), which has a poor prognosis and frequently recurs after the first resection. Therefore, more sensitive diagnostic tools and effective therapeutic methods are urgently needed. MicroRNAs (miRNAs) are small noncoding RNAs that regulate the expression of protein-coding genes by repressing their translation or cleaving RNA transcripts in a sequence-specific manner. miRNAs play very important roles in regulating genes related to tumorigenesis, tumor development, progression, metastasis and angiogenesis. With the rapid development of high-throughput sequencing technology, an increasing number of miRNAs with aberrant expression between either BC patients and healthy volunteers or between BC tumor tissues and matched peripheral control tissues have been recently examined. The tumor etiopathogenesis must be determined to promote the development of new markers as diagnostic and prognostic tools and targets for bladder tumor therapy, it is therefore vital to elucidate the function of miRNAs with aberrant expression in BC. In the present study, we examined the published data of BC-related miRNAs by reviewing their expression levels, possible functions, potential target genes, related molecular regulatory networks, candidate markers for prognosis and diagnosis, and prospective therapeutic cases, and we summarized the status of research on BC-related miRNAs in recent years.
Collapse
|
|
22
|
Sharifi H, Shafiee A, Molavi G, Razi E, Mousavi N, Sarvizadeh M, Taghizadeh M. Leukemia-derived exosomes: Bringing oncogenic signals to blood cells. J Cell Biochem 2019; 120:16307-16315. [PMID: 31127656 DOI: 10.1002/jcb.29018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 04/11/2019] [Accepted: 04/18/2019] [Indexed: 12/26/2022]
Abstract
Leukemia is a cancer, which is derived from leukocytes and precursors of leukocytes in the bone marrow. A large number of pivotal biological processes are linked to leukemia pathogenesis. More insights into these mechanisms can provide a better developing pharmacological platform for patients with leukemia. Among the different players in leukemia pathogenesis, exosomes have appeared as a new biological vehicle, which can transfer oncogenic signals to blood cells. Exosomes are nano-carriers, which enable transferring numerous cargos such as DNA fragments, RNAs, messenger RNAs, microRNAs, long noncoding RNA, and proteins. Targeting the contents of exosomes leads to the alteration of host cell behavior. Increasing evidence has indicated that leukemia-derived exosomes could be utilized as prognostic, diagnostic, and therapeutic biomarkers for individuals suffering from leukemia. In this regard, the importance of exosomes in terms of initiation and progression of leukemia was underlined in this study.
Collapse
Affiliation(s)
- Hossein Sharifi
- The Advocate Center for Clinical Research, Ayatollah Yasrebi Hospital, Kashan, Iran
| | - Alimohammad Shafiee
- Division of General Internal Medicine, Toronto General Hospital, Toronto, Canada
| | - Ghader Molavi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ebrahim Razi
- The Advocate Center for Clinical Research, Ayatollah Yasrebi Hospital, Kashan, Iran
| | - Nousin Mousavi
- Department of Surgery, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mostafa Sarvizadeh
- The Advocate Center for Clinical Research, Ayatollah Yasrebi Hospital, Kashan, Iran
| | - Mohsen Taghizadeh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| |
Collapse
|
|
23
|
Fuji T, Umeda Y, Nyuya A, Taniguchi F, Kawai T, Yasui K, Toshima T, Yoshida K, Fujiwara T, Goel A, Nagasaka T. Detection of circulating microRNAs with Ago2 complexes to monitor the tumor dynamics of colorectal cancer patients during chemotherapy. Int J Cancer 2019; 144:2169-2180. [PMID: 30381824 PMCID: PMC6590166 DOI: 10.1002/ijc.31960] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 09/07/2018] [Accepted: 09/21/2018] [Indexed: 01/18/2023]
Abstract
Because of the different forms of circulating miRNAs in plasma, Argonaute2 (Ago2)-miRNAs and extracellular vesicles (EV-miRNAs), we examined the two forms of extracellular miRNAs in vitro and developed a unique methodology to detect circulating Ago2-miRNAs in small volumes of plasma. We demonstrated that Ago2-miR-21 could be released into the extracellular fluid by active export from viable cancer cells and cytolysis in vitro. As miR-21 and miR-200c were abundantly expressed in both metastatic liver sites and primary lesions, we evaluated Ago2-miR-21 as a candidate biomarker of both active export and cytolysis while Ago2-miR-200c as a biomarker of cytolysis in plasma obtained from colorectal cancer (CRC) patients before treatment and in a series of plasma obtained from CRC patients with liver metastasis who received systemic chemotherapy. The measurement of Ago2-miR-21 allowed us to distinguish CRC patients from subjects without CRC. The trend in ΔCt values for Ago2-miR-21 and -200c during chemotherapy could predict tumor response to ongoing treatment. Thus, capturing circulating Ago2-miRNAs from active export can screen patients with tumor burdens, while capturing them from passive release by cytolysis can monitor tumor dynamics during chemotherapy treatment.
Collapse
Affiliation(s)
- Tomokazu Fuji
- Department of Gastroenterological SurgeryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
| | - Yuzo Umeda
- Department of Gastroenterological SurgeryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
| | - Akihiro Nyuya
- Department of Gastroenterological SurgeryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
- Department of Clinical OncologyKawasaki Medical SchoolKurashikiJapan
| | - Fumitaka Taniguchi
- Department of Gastroenterological SurgeryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
| | - Takashi Kawai
- Department of Gastroenterological SurgeryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
| | - Kazuya Yasui
- Department of Gastroenterological SurgeryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
| | - Toshiaki Toshima
- Department of Gastroenterological SurgeryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
| | - Kazuhiro Yoshida
- Department of Gastroenterological SurgeryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
- Center for Gastrointestinal Research; Center for Translational Genomics and OncologyBaylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical CenterDallasTX
| | - Toshiyoshi Fujiwara
- Department of Gastroenterological SurgeryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
| | - Ajay Goel
- Center for Gastrointestinal Research; Center for Translational Genomics and OncologyBaylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical CenterDallasTX
| | - Takeshi Nagasaka
- Department of Gastroenterological SurgeryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
- Department of Clinical OncologyKawasaki Medical SchoolKurashikiJapan
| |
Collapse
|
|
24
|
Bai H, Lei K, Huang F, Jiang Z, Zhou X. Exo-circRNAs: a new paradigm for anticancer therapy. Mol Cancer 2019; 18:56. [PMID: 30925885 PMCID: PMC6441195 DOI: 10.1186/s12943-019-0986-2] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 02/25/2019] [Indexed: 02/05/2023] Open
Abstract
CircRNAs, as new members of long noncoding RNAs, have been the focus of recent investigation. CircRNAs feature a closed continuous loop structure without 5′-3′ polarity or a poly A tail. Many studies have reported the potential application of circRNAs in the clinic as new biomarkers and therapeutic targets in different diseases, especially for cancer. Additionally, the exosomes are important vehicles in cell-to-cell communication. And exo-circRNAs are circRNAs in exosomes which can be detected to provide additional evidence for conventional diagnostic methods and can be applied to suppress the malignant progress in cancer. In this review, we describe the biogenesis, characteristics, and functions of circRNAs and exosomes. Specifically, we present a comprehensive update of the promising role of exo-circRNAs in anticancer therapy.
Collapse
Affiliation(s)
- Hetian Bai
- National Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.,State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Kexin Lei
- National Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.,State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Fei Huang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zhou Jiang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xikun Zhou
- National Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
| |
Collapse
|
|
25
|
Liu S, Zhan Y, Luo J, Feng J, Lu J, Zheng H, Wen Q, Fan S. Roles of exosomes in the carcinogenesis and clinical therapy of non-small cell lung cancer. Biomed Pharmacother 2019; 111:338-346. [DOI: 10.1016/j.biopha.2018.12.088] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 12/06/2018] [Accepted: 12/19/2018] [Indexed: 02/06/2023] Open
|
|
26
|
Transfer of Extracellular Vesicle-Associated-RNAs Induces Drug Resistance in ALK-Translocated Lung Adenocarcinoma. Cancers (Basel) 2019; 11:cancers11010104. [PMID: 30658414 PMCID: PMC6356387 DOI: 10.3390/cancers11010104] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 01/11/2019] [Accepted: 01/14/2019] [Indexed: 12/18/2022] Open
Abstract
Anaplastic lymphoma kinase (ALK) translocation is an actionable mutation in lung adenocarcinoma. Nonetheless tumour consists of heterogeneous cell subpopulations with diverse phenotypes and genotypes, and cancer cells can actively release extracellular vesicles (EVs) to modulate the phenotype of other cells in the tumour microenvironment. We hypothesized that EVs derived from a drug-resistant subpopulation of cells could induce drug resistance in recipient cells. We have established ALK-translocated lung adenocarcinoma cell lines and subclones. The subclones have been characterized and the expression of EV-RNAs determined by quantitative polymerase chain reaction. The effects of EV transfer on drug resistance were examined in vitro. Serum EV-RNA was assayed serially in two patients prescribed ALK-tyrosine kinase inhibitor (ALK-TKI) treatment. We demonstrated that the EVs from an ALK-TKI-resistant subclone could induce drug resistance in the originally sensitive subclone. EV-RNA profiling revealed that miRNAs miR-21-5p and miR-486-3p, and lncRNAs MEG3 and XIST were differentially expressed in the EVs secreted by the resistant subclones. These circulating EV-RNA levels have been found to correlate with disease progression of EML4-ALK-translocated lung adenocarcinoma in patients prescribed ALK-TKI treatment. The results from this study suggest that EVs released by a drug-resistant subpopulation can induce drug resistance in other subpopulations and may sustain intratumoural heterogeneity.
Collapse
|
|
27
|
Santoni G, Morelli MB, Amantini C, Battelli N. Urinary Markers in Bladder Cancer: An Update. Front Oncol 2018; 8:362. [PMID: 30245975 PMCID: PMC6137202 DOI: 10.3389/fonc.2018.00362] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 08/16/2018] [Indexed: 12/12/2022] Open
Abstract
Bladder cancer (BC) is ones of the most common cancer worldwide. It is classified in muscle invasive (MIBC) and muscle non-invasive (NMIBC) BC. NMIBCs frequently recur and progress to MIBCs with a reduced survival rate and frequent distant metastasis. BC detection require unpleasant and expensive cystoscopy and biopsy, which are often accompanied by several adverse effects. Thus, there is an urgent need to develop novel diagnostic methods for initial detection and surveillance in both MIBCs and NMIBCs. Multiple urine-based tests approved by FDA for BC detection and surveillance are commercially available. However, at present, sensitivity, specificity and diagnostic accuracy of these urine-based assays are still suboptimal and, in the attend to improve them, novel molecular markers as well as multiple-assays must to be translated in clinic. Now there are growing evidence toward the use of minimally invasive “liquid biopsy” to identify biomarkers in urologic malignancy. DNA- and RNA-based markers in body fluids such as blood and urine are promising potential markers in diagnostic, prognostic, predictive and monitoring urological malignancies. Thus, circulating cell-free DNA, DNA methylation and mutations, circulating tumor cells, miRNA, IncRNA and mRNAs, cell-free proteins and peptides, and exosomes have been assessed in urine specimens. However, proteomic and genomic data must to be validated in well-designed multicenter clinical studies, before to be employed in clinic oncology.
Collapse
Affiliation(s)
- Giorgio Santoni
- Immunopathology Laboratory, School of Pharmacy, University of Camerino, Camerino, Italy
| | - Maria B Morelli
- Immunopathology Laboratory, School of Pharmacy, University of Camerino, Camerino, Italy.,Immunopathology Laboratory, School of Biosciences, Biotechnology and Veterinary Medicine, University of Camerino, Camerino, Italy
| | - Consuelo Amantini
- Immunopathology Laboratory, School of Biosciences, Biotechnology and Veterinary Medicine, University of Camerino, Camerino, Italy
| | | |
Collapse
|
|
28
|
Zhang J, Wang W, Chen S, Wang Y, Xia S. Distinct non-invasive evaluation values of tumor-derived cell-free microRNAs, circulating microvesicles and exosomal microRNAs after renal carcinoma cryoablation. Biochem Biophys Res Commun 2018; 503:1278-1283. [PMID: 30017193 DOI: 10.1016/j.bbrc.2018.07.037] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 07/07/2018] [Indexed: 12/11/2022]
Abstract
The detection of peripheral circulating tumor-derived components, such as cell-free microRNAs, circulating microvesicles, and exosomal microRNAs, has been shown as a promising noninvasive strategy. However, the different roles of these components in tumor therapy evaluations have remained largely undefined. In this paper, we employed an in vivo model of the human clear cell renal cell carcinoma line Caki-1-bearing mice to evaluate the therapeutic effects of cryoablation, which is a new minimally invasive treatment for renal cell carcinoma. At different times after cryoablation, we found that the levels of the cell-free microRNAs miR-122, miR-155 and miR-210 were first increased and then decreased. Additionally, the number of large-sized microvesicles was increased after cryoablation, but the number of small-sized circulating microvesicles did not change. Furthermore, the exosomal microRNAs miR-126-3p, miR-17-5p, and miR-21-3p rapidly decreased one day after cryoablation, an effect that was well correlated with the treatment degree. Therefore, we suggest that these circulating components may have different levels of importance in the evaluation of the efficacy of renal cell cryoablation, furthermore, exosomal microRNAs may be more suitable for the early postoperative judgment of tumor elimination effects, which are worth further exploration in clinical practice.
Collapse
Affiliation(s)
- Jie Zhang
- Department of Urology, Shanghai General Hospital of Nanjing Medical University, China; Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Wenbin Wang
- Department of Urology, Shanghai General Hospital of Nanjing Medical University, China; Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Shasha Chen
- Center of Translational Medicine Research, Second Military Medical University, China
| | - Yue Wang
- Center of Translational Medicine Research, Second Military Medical University, China
| | - Shujie Xia
- Department of Urology, Shanghai General Hospital of Nanjing Medical University, China; Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China.
| |
Collapse
|
|
29
|
Rolfo C, Mack PC, Scagliotti GV, Baas P, Barlesi F, Bivona TG, Herbst RS, Mok TS, Peled N, Pirker R, Raez LE, Reck M, Riess JW, Sequist LV, Shepherd FA, Sholl LM, Tan DSW, Wakelee HA, Wistuba II, Wynes MW, Carbone DP, Hirsch FR, Gandara DR. Liquid Biopsy for Advanced Non-Small Cell Lung Cancer (NSCLC): A Statement Paper from the IASLC. J Thorac Oncol 2018; 13:1248-1268. [PMID: 29885479 DOI: 10.1016/j.jtho.2018.05.030] [Citation(s) in RCA: 457] [Impact Index Per Article: 65.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 05/16/2018] [Accepted: 05/26/2018] [Indexed: 12/16/2022]
Abstract
The isolation and analysis of circulating cell-free tumor DNA in plasma is a powerful tool with considerable potential to improve clinical outcomes across multiple cancer types, including NSCLC. Assays of this nature that use blood as opposed to tumor samples are frequently referred to as liquid biopsies. An increasing number of innovative platforms have been recently developed that improve not only the fidelity of the molecular analysis but also the number of tests performed on a single specimen. Circulating tumor DNA assays for detection of both EGFR sensitizing and resistance mutations have already entered clinical practice and many other molecular tests - such as detection of resistance mutations for Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase rearrangements - are likely to do so in the near future. Due to an abundance of new evidence, an appraisal was warranted to review strengths and weaknesses, to describe what is already in clinical practice and what has yet to be implemented, and to highlight areas in need of further investigation. A multidisciplinary panel of experts in the field of thoracic oncology with interest and expertise in liquid biopsy and molecular pathology was convened by the International Association for the Study of Lung Cancer to evaluate current available evidence with the aim of producing a set of recommendations for the use of liquid biopsy for molecular analysis in guiding the clinical management of advanced NSCLC patients as well as identifying unmet needs. In summary, the panel concluded that liquid biopsy approaches have significant potential to improve patient care, and immediate implementation in the clinic is justified in a number of therapeutic settings relevant to NSCLC.
Collapse
Affiliation(s)
- Christian Rolfo
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
| | - Philip C Mack
- University of California Davis Comprehensive Cancer Center, Sacramento, California
| | - Giorgio V Scagliotti
- University of Turin, Department of Oncology at San Luigi Hospital, Orbassano, Italy
| | - Paul Baas
- Department of Thoracic Oncology, The Netherlands Cancer Institute and Department of Pulmonary Disease, Academic Medical Center, Amsterdam, The Netherlands
| | - Fabrice Barlesi
- Multidisciplinary Oncology and Therapeutic Innovations Department, Assistance Publique Hôpitaux de Marseille, Aix Marseille University, Marseille, France
| | - Trever G Bivona
- Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California
| | | | - Tony S Mok
- State Key Laboratory of South China, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Nir Peled
- Institute of Oncology, Soroka Medical Center and Ben Gurion University, Beer Sheva, Israel
| | - Robert Pirker
- Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Luis E Raez
- Memorial Cancer Institute, Memorial Healthcare System/Florida International University (FIU) Miami, Florida
| | - Martin Reck
- Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany
| | - Jonathan W Riess
- University of California Davis Comprehensive Cancer Center, Sacramento, California
| | - Lecia V Sequist
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Frances A Shepherd
- University Health Network and Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Lynette M Sholl
- Brigham and Women's Hospital and Department of Pathology, Harvard Medical School, Boston, Massachusetts
| | - Daniel S W Tan
- National Cancer Centre Singapore and Genome Institute of Singapore, Singapore
| | - Heather A Wakelee
- Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California
| | - Ignacio I Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Murry W Wynes
- International Association for the Study of Lung Cancer, Aurora, Colorado
| | - David P Carbone
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - Fred R Hirsch
- Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, and the International Association for the Study of Lung Cancer, Aurora, Colorado.
| | - David R Gandara
- University of California Davis Comprehensive Cancer Center, Sacramento, California
| |
Collapse
|
|
30
|
Peng J, Wang W, Hua S, Liu L. Roles of Extracellular Vesicles in Metastatic Breast Cancer. BREAST CANCER-BASIC AND CLINICAL RESEARCH 2018; 12:1178223418767666. [PMID: 29881285 PMCID: PMC5987895 DOI: 10.1177/1178223418767666] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 10/27/2018] [Indexed: 01/29/2023]
Abstract
Cells can secrete extracellular vesicles (EVs) to communicate with neighboring or
distant cells by EVs which are composed of a lipid bilayer containing
transmembrane proteins and enclosing cytosolic proteins, lipids, and nucleic
acids. Breast Cancer is the most frequently diagnosed malignancy with more than
1 million new cases each year and ranks the leading cause of cancer mortality in
women worldwide. In this review, we will discuss recent progresses of the roles
and mechanisms of cancer-derived EVs in metastatic breast cancer, with a special
attention on tumor microenvironment construction, progression, and
chemo/radiotherapy responses. This review also covers EV roles as biomarker and
therapeutic target in clinical application.
Collapse
Affiliation(s)
- Junya Peng
- Department of Center Lab, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China
| | - Wenqian Wang
- School of Medicine, Tsinghua University, Beijing, China
| | - Surong Hua
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China
| | - Lulu Liu
- Department of Center Lab, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China
| |
Collapse
|
|
31
|
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.
Collapse
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.
| |
Collapse
|
|
32
|
Wu X, Guo B, Sheng Y, Zhang Y, Wang J, Peng S, Liu L, Wu HC. Multiplexed discrimination of microRNA single nucleotide variants through triplex molecular beacon sensors. Chem Commun (Camb) 2018; 54:7673-7676. [DOI: 10.1039/c8cc03574a] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Herein, we develop a new nanopore sensing strategy for the selective detection of microRNAs and single nucleotide variants (SNVs) based on triplex molecular beacon sensors.
Collapse
Affiliation(s)
- Xiaoyuan Wu
- School of Resource and Environmental Engineering
- Hefei University of Technology
- Hefei 230009
- China
- Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, Multidisciplinary Center
| | - Bingyuan Guo
- Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, Multidisciplinary Center
- Institute of High Energy Physics
- Chinese Academy of Sciences
- Beijing 100049
- China
| | - Yingying Sheng
- Beijing National Laboratory for Molecular Sciences
- Key Laboratory of Analytical Chemistry for Living Biosystems
- Institute of Chemistry, Chinese Academy of Sciences
- Beijing 100190
- China
| | - Yun Zhang
- Beijing National Laboratory for Molecular Sciences
- Key Laboratory of Analytical Chemistry for Living Biosystems
- Institute of Chemistry, Chinese Academy of Sciences
- Beijing 100190
- China
| | - Jin Wang
- School of Resource and Environmental Engineering
- Hefei University of Technology
- Hefei 230009
- China
| | - Shuchuan Peng
- School of Resource and Environmental Engineering
- Hefei University of Technology
- Hefei 230009
- China
| | - Lei Liu
- Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, Multidisciplinary Center
- Institute of High Energy Physics
- Chinese Academy of Sciences
- Beijing 100049
- China
| | - Hai-Chen Wu
- Beijing National Laboratory for Molecular Sciences
- Key Laboratory of Analytical Chemistry for Living Biosystems
- Institute of Chemistry, Chinese Academy of Sciences
- Beijing 100190
- China
| |
Collapse
|
|
33
|
Crouser ED, Hamzeh NY, Maier LA, Julian MW, Gillespie M, Rahman M, Baxter D, Wu X, Nana-Sinkam SP, Wang K. Exosomal MicroRNA for Detection of Cardiac Sarcoidosis. Am J Respir Crit Care Med 2017; 196:931-934. [PMID: 28245138 DOI: 10.1164/rccm.201611-2183le] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
| | | | | | - Mark W Julian
- 1 Ohio State University Wexner Medical Center Columbus, Ohio
| | | | - Mohammad Rahman
- 1 Ohio State University Wexner Medical Center Columbus, Ohio
| | - David Baxter
- 3 Institute for Systems Biology Seattle, Washington and
| | - Xiaogang Wu
- 3 Institute for Systems Biology Seattle, Washington and
| | | | - Kai Wang
- 3 Institute for Systems Biology Seattle, Washington and
| |
Collapse
|
|
34
|
Ding Y, Zhao R, Zhao X, Matthay MA, Nie HG, Ji HL. ENaCs as Both Effectors and Regulators of MiRNAs in Lung Epithelial Development and Regeneration. Cell Physiol Biochem 2017; 44:1120-1132. [PMID: 29179210 PMCID: PMC5884700 DOI: 10.1159/000485417] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 10/14/2017] [Indexed: 12/14/2022] Open
Abstract
Epithelial sodium channels (ENaC) play an important role in re-absorbing excessive luminal fluid by building up an osmotic Na+ gradient across the tight epithelium in the airway, the lung, the kidney, and the colon. The ENaC is a major pathway for retention of salt in kidney too. MicroRNAs (miRs), a group of non-coding RNAs that regulate gene expression at the post-transcriptional level, have emerged as a novel class of regulators for ENaC. Given the ENaC pathway is crucial for maintaining fluid homeostasis in the lung and the kidney and other cavities, we summarized the cross-talk between ENaC and miRs and recapitulated the underlying regulatory factors, including aldosterone, transforming growth factor-β1, and vascular endothelial growth factor-A in the lung and other epithelial tissues/organs. We have compared the profiling of miRs between normal and injured mice and human lungs, which showed a significant alteration in numerous miRs in mouse models of LPS and ventilator induced ARDS. In addition, we reiterated the potential regulation of the ENaC by miRs in stem/ progenitor cell-based re-epithelialization, and identified a promising pharmaceutic target of ENaC for removing edema fluid in ARDS by mesenchymal stem cells-released paracrine. In conclusion, it seems that the interactions between miRs and scnn1s/ENaCs are critical for lung development, epithelial cell turnover in adult lungs, and re-epithelialization for repair.
Collapse
Affiliation(s)
- Yan Ding
- Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, China
| | - Runzhen Zhao
- Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler Texas
- Texas Lung Injury Institute, University of Texas Health Northeast, Tyler Texas, USA
| | - Xiaoli Zhao
- Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia, USA
| | - Michael A. Matthay
- Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California, USA
| | - Hong-Guang Nie
- Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, China
| | - Hong-Long Ji
- Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, China
- Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler Texas
- Texas Lung Injury Institute, University of Texas Health Northeast, Tyler Texas, USA
| |
Collapse
|
|
35
|
Wu D, Ni J, Beretov J, Cozzi P, Willcox M, Wasinger V, Walsh B, Graham P, Li Y. Urinary biomarkers in prostate cancer detection and monitoring progression. Crit Rev Oncol Hematol 2017; 118:15-26. [DOI: 10.1016/j.critrevonc.2017.08.002] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 08/08/2017] [Accepted: 08/11/2017] [Indexed: 12/21/2022] Open
|
|
36
|
San-Millán I, Brooks GA. Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg Effect. Carcinogenesis 2017; 38:119-133. [PMID: 27993896 PMCID: PMC5862360 DOI: 10.1093/carcin/bgw127] [Citation(s) in RCA: 256] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 12/08/2016] [Indexed: 12/15/2022] Open
Abstract
Herein, we use lessons learned in exercise physiology and metabolism to propose that augmented lactate production (‘lactagenesis’), initiated by gene mutations, is the reason and purpose of the Warburg Effect and that dysregulated lactate metabolism and signaling are the key elements in carcinogenesis. Lactate-producing (‘lactagenic’) cancer cells are characterized by increased aerobic glycolysis and excessive lactate formation, a phenomenon described by Otto Warburg 93 years ago, which still remains unexplained. After a hiatus of several decades, interest in lactate as a player in cancer has been renewed. In normal physiology, lactate, the obligatory product of glycolysis, is an important metabolic fuel energy source, the most important gluconeogenic precursor, and a signaling molecule (i.e. a ‘lactormone’) with major regulatory properties. In lactagenic cancers, oncogenes and tumor suppressor mutations behave in a highly orchestrated manner, apparently with the purpose of increasing glucose utilization for lactagenesis purposes and lactate exchange between, within and among cells. Five main steps are identified (i) increased glucose uptake, (ii) increased glycolytic enzyme expression and activity, (iii) decreased mitochondrial function, (iv) increased lactate production, accumulation and release and (v) upregulation of monocarboxylate transporters MTC1 and MCT4 for lactate exchange. Lactate is probably the only metabolic compound involved and necessary in all main sequela for carcinogenesis, specifically: angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism. We hypothesize that lactagenesis for carcinogenesis is the explanation and purpose of the Warburg Effect. Accordingly, therapies to limit lactate exchange and signaling within and among cancer cells should be priorities for discovery.
Collapse
Affiliation(s)
- Iñigo San-Millán
- Department of Physical Medicine and Rehabilitation, University of Colorado School of Medicine, Aurora, CO 80045, USA.,Physiology Laboratory, CU Sports Medicine and Performance Center, Boulder, CO 80309, USA and
| | - George A Brooks
- Department of Integrative Biology, University of California, Berkeley, CA 94720, USA
| |
Collapse
|
|
37
|
Jin X, Chen Y, Chen H, Fei S, Chen D, Cai X, Liu L, Lin B, Su H, Zhao L, Su M, Pan H, Shen L, Xie D, Xie C. Evaluation of Tumor-Derived Exosomal miRNA as Potential Diagnostic Biomarkers for Early-Stage Non-Small Cell Lung Cancer Using Next-Generation Sequencing. Clin Cancer Res 2017; 23:5311-5319. [PMID: 28606918 DOI: 10.1158/1078-0432.ccr-17-0577] [Citation(s) in RCA: 404] [Impact Index Per Article: 50.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Revised: 05/10/2017] [Accepted: 06/05/2017] [Indexed: 12/19/2022]
Abstract
Purpose: To identify tumor-derived exosomal biomarkers that are able to discriminate between adenocarcinoma and squamous cell carcinoma (SCC) as a noninvasive method in the early diagnosis of non-small cell lung cancer (NSCLC).Experimental Design: Tumor-derived exosomes from the plasma of early-stage NSCLC patients were isolated. Exosomal miRNA profiling of 46 stage I NSCLC patients and 42 healthy individuals was performed using miRNA-seq to identify and validate adenocarcinoma- and SCC-specific miRNAs. The diagnostic accuracy of select miRNAs was tested further with an additional 60 individuals.Results: There were 11 and 6 miRNAs expressed at remarkably higher levels, 13 and 8 miRNAs expressed at lower levels in adenocarcinoma and SCC patients, respectively, compared with healthy volunteers. Distinct adenocarcinoma- and SCC-specific exosomal miRNAs were validated. The reliability of miRNA-seq data was verified with several demonstrated diagnostic potential miRNAs for NSCLC and other carcinomas, as reported in previous studies, such as let-7, miR-21, miR-24, and miR-486. The results indicated that miR-181-5p, miR-30a-3p, miR-30e-3p, and miR-361-5p were adenocarcinoma-specific, and miR-10b-5p, miR-15b-5p, and miR-320b were SCC-specific. The diagnostic accuracy of three combination miRNA panels was evaluated using an AUC value of 0.899, 0.936, and 0.911 for detecting NSCLC, adenocarcinoma, and SCC, respectively.Conclusions: Tumor-derived exosomal miRNAs, adenocarcinoma-specific miR-181-5p, miR-30a-3p, miR-30e-3p and miR-361-5p, and SCC-specific miR-10b-5p, miR-15b-5p, and miR-320b were observed by next-generation sequencing, and their diagnostic accuracy were verified. These miRNAs may be promising and effective candidates in the development of highly sensitive, noninvasive biomarkers for early NSCLC diagnosis. Clin Cancer Res; 23(17); 5311-9. ©2017 AACR.
Collapse
Affiliation(s)
- Xiance Jin
- Department of Radiotherapy and Chemotherapy, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yanfan Chen
- Department of Respiratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hanbin Chen
- Department of Radiotherapy and Chemotherapy, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shaoran Fei
- Department of Radiotherapy and Chemotherapy, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Didi Chen
- Department of Radiotherapy and Chemotherapy, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaona Cai
- Department of Radiotherapy and Chemotherapy, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Linger Liu
- Department of Radiotherapy and Chemotherapy, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Baochai Lin
- Department of Radiotherapy and Chemotherapy, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Huafang Su
- Department of Radiotherapy and Chemotherapy, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lihao Zhao
- Department of Radiotherapy and Chemotherapy, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Meng Su
- Department of Radiotherapy and Chemotherapy, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Huanle Pan
- Department of Radiotherapy and Chemotherapy, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lanxiao Shen
- Department of Radiotherapy and Chemotherapy, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Deyao Xie
- Department of Thoracic Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Congying Xie
- Department of Radiotherapy and Chemotherapy, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| |
Collapse
|
|
38
|
Mirzaei H, Sahebkar A, Jaafari MR, Goodarzi M, Mirzaei HR. Diagnostic and Therapeutic Potential of Exosomes in Cancer: The Beginning of a New Tale? J Cell Physiol 2017; 232:3251-3260. [PMID: 27966794 DOI: 10.1002/jcp.25739] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Accepted: 12/13/2016] [Indexed: 12/21/2022]
Abstract
Exosomes have emerged as one of the main players in intercellular communication. These small nano-sized particles have many roles in various physiological pathways in normal and abnormal cells. Exosomes can carry various cargos such as proteins, mRNAs, and miRNAs to recipient cells. Uptake of exosomes and their cargo can induce and/or inhibit different cellular and molecular pathways that lead to the alteration of cell behavior. Multiple lines of evidence have indicated that exosomes released from cancer cells can effect development of cancer in different stages. These particles and their cargo could regulate different processes such as tumor growth, metastasis, drug resistance, angiogenesis, and immune system functioning. It has been observed that exosomes can be used as potential diagnostic biomarkers in various cancer types. Moreover, some studies have used these particles as biological vehicles for delivery of various drugs such as doxorubicin, siRNAs, and miRNAs. Here, we summarized the findings on the role of exosomes in different pathological processes involved in cancer. Moreover, application of these particles as diagnostic and therapeutic biomarkers in different types of cancers is discussed. J. Cell. Physiol. 232: 3251-3260, 2017. © 2016 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Hamed Mirzaei
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Reza Jaafari
- Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Goodarzi
- Faculty of Bioscience Engineering, Department of Biosystems, Katholieke Universiteit Leuven-KU Leuven, Heverlee, Belgium
| | - Hamid Reza Mirzaei
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
39
|
Di Meo A, Bartlett J, Cheng Y, Pasic MD, Yousef GM. Liquid biopsy: a step forward towards precision medicine in urologic malignancies. Mol Cancer 2017; 16:80. [PMID: 28410618 PMCID: PMC5391592 DOI: 10.1186/s12943-017-0644-5] [Citation(s) in RCA: 250] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 03/28/2017] [Indexed: 12/12/2022] Open
Abstract
There is a growing trend towards exploring the use of a minimally invasive "liquid biopsy" to identify biomarkers in a number of cancers, including urologic malignancies. Multiple aspects can be assessed in circulating cell-free DNA, including cell-free DNA levels, integrity, methylation and mutations. Other prospective liquid biopsy markers include circulating tumor cells, circulating RNAs (miRNA, lncRNAs and mRNAs), cell-free proteins, peptides and exosomes have also emerged as non-invasive cancer biomarkers. These circulating molecules can be detected in various biological fluids, including blood, urine, saliva and seminal plasma. Liquid biopsies hold great promise for personalized medicine due to their ability to provide multiple non-invasive global snapshots of the primary and metastatic tumors. Molecular profiling of circulating molecules has been a stepping-stone to the successful introduction of several non-invasive multi-marker tests into the clinic. In this review, we provide an overview of the current state of cell-free DNA-based kidney, prostate and bladder cancer biomarker research and discuss the potential utility other circulating molecules. We will also discuss the challenges and limitations facing non-invasive cancer biomarker discovery and the benefits of this growing area of translational research.
Collapse
Affiliation(s)
- Ashley Di Meo
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada
| | - Jenni Bartlett
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada
| | - Yufeng Cheng
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Maria D Pasic
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Department of Laboratory Medicine, St. Joseph's Health Centre, Toronto, ON, Canada
| | - George M Yousef
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. .,Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.
| |
Collapse
|
|
40
|
Bach DH, Hong JY, Park HJ, Lee SK. The role of exosomes and miRNAs in drug-resistance of cancer cells. Int J Cancer 2017; 141:220-230. [PMID: 28240776 DOI: 10.1002/ijc.30669] [Citation(s) in RCA: 212] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 02/08/2017] [Accepted: 02/20/2017] [Indexed: 12/14/2022]
Abstract
Chemotherapy, one of the principal approaches for cancer patients, plays a crucial role in controlling tumor progression. Clinically, tumors reveal a satisfactory response following the first exposure to the chemotherapeutic drugs in treatment. However, most tumors sooner or later become resistant to even chemically unrelated anticancer agents after repeated treatment. The reduced drug accumulation in tumor cells is considered one of the significant mechanisms by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell membrane. The mechanisms of treatment failure of chemotherapeutic drugs have been investigated, including drug efflux, which is mediated by extracellular vesicles (EVs). Exosomes, a subset of EVs with a size range of 40-150 nm and a lipid bilayer membrane, can be released by all cell types. They mediate specific cell-to-cell interactions and activate signaling pathways in cells they either fuse with or interact with, including cancer cells. Exosomal RNAs are heterogeneous in size but enriched in small RNAs, such as miRNAs. In the primary tumor microenvironment, cancer-secreted exosomes and miRNAs can be internalized by other cell types. MiRNAs loaded in these exosomes might be transferred to recipient niche cells to exert genome-wide regulation of gene expression. How exosomal miRNAs contribute to the development of drug resistance in the context of the tumor microenvironment has not been fully described. In this review, we will highlight recent studies regarding EV-mediated microRNA delivery in formatting drug resistance. We also suggest the use of EVs as an advancing method in antiresistance treatment.
Collapse
Affiliation(s)
- Duc-Hiep Bach
- College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul, Republic of Korea
| | - Ji-Young Hong
- College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul, Republic of Korea
| | - Hyen Joo Park
- College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul, Republic of Korea
| | - Sang Kook Lee
- College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul, Republic of Korea
| |
Collapse
|
|
41
|
Inamdar S, Nitiyanandan R, Rege K. Emerging applications of exosomes in cancer therapeutics and diagnostics. Bioeng Transl Med 2017; 2:70-80. [PMID: 28529978 PMCID: PMC5413841 DOI: 10.1002/btm2.10059] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 02/26/2017] [Accepted: 03/06/2017] [Indexed: 12/21/2022] Open
Abstract
Exosomes are nanoscale extracellular vesicles that are shed from different cells in the body. Exosomes encapsulate several biomolecules including lipids, proteins, and nucleic acids, and can therefore play a key role in cellular communication. These vesicles can be isolated from different body fluids and their small sizes make them attractive in various biomedical applications. Here, we review state-of-the art approaches in exosome isolation and purification, and describe their potential use in cancer vaccines, drug delivery, and diagnostics.
Collapse
Affiliation(s)
- Sahil Inamdar
- Chemical EngineeringArizona State UniversityTempeAZ 85287
| | | | - Kaushal Rege
- Chemical EngineeringArizona State UniversityTempeAZ 85287
| |
Collapse
|
|
42
|
Molina-Vila MA, Mayo-de-Las-Casas C, Giménez-Capitán A, Jordana-Ariza N, Garzón M, Balada A, Villatoro S, Teixidó C, García-Peláez B, Aguado C, Catalán MJ, Campos R, Pérez-Rosado A, Bertran-Alamillo J, Martínez-Bueno A, Gil MDLL, González-Cao M, González X, Morales-Espinosa D, Viteri S, Karachaliou N, Rosell R. Liquid Biopsy in Non-Small Cell Lung Cancer. Front Med (Lausanne) 2016; 3:69. [PMID: 28066769 PMCID: PMC5179978 DOI: 10.3389/fmed.2016.00069] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 12/08/2016] [Indexed: 12/24/2022] Open
Abstract
Liquid biopsy analyses are already incorporated in the routine clinical practice in many hospitals and oncology departments worldwide, improving the selection of treatments and monitoring of lung cancer patients. Although they have not yet reached its full potential, liquid biopsy-based tests will soon be as widespread as “standard” biopsies and imaging techniques, offering invaluable diagnostic, prognostic, and predictive information. This review summarizes the techniques available for the isolation and analysis of circulating free DNA and RNA, exosomes, tumor-educated platelets, and circulating tumor cells from the blood of cancer patients, presents the methodological challenges associated with each of these materials, and discusses the clinical applications of liquid biopsy testing in lung cancer.
Collapse
Affiliation(s)
- Miguel A Molina-Vila
- Laboratory of Oncology, Pangaea Biotech, Quirón Dexeus University Hospital , Barcelona , Spain
| | - Clara Mayo-de-Las-Casas
- Laboratory of Oncology, Pangaea Biotech, Quirón Dexeus University Hospital , Barcelona , Spain
| | - Ana Giménez-Capitán
- Laboratory of Oncology, Pangaea Biotech, Quirón Dexeus University Hospital , Barcelona , Spain
| | - Núria Jordana-Ariza
- Laboratory of Oncology, Pangaea Biotech, Quirón Dexeus University Hospital , Barcelona , Spain
| | - Mónica Garzón
- Laboratory of Oncology, Pangaea Biotech, Quirón Dexeus University Hospital , Barcelona , Spain
| | - Ariadna Balada
- Laboratory of Oncology, Pangaea Biotech, Quirón Dexeus University Hospital , Barcelona , Spain
| | - Sergi Villatoro
- Laboratory of Oncology, Pangaea Biotech, Quirón Dexeus University Hospital , Barcelona , Spain
| | - Cristina Teixidó
- Laboratory of Oncology, Pangaea Biotech, Quirón Dexeus University Hospital , Barcelona , Spain
| | - Beatriz García-Peláez
- Laboratory of Oncology, Pangaea Biotech, Quirón Dexeus University Hospital , Barcelona , Spain
| | - Cristina Aguado
- Laboratory of Oncology, Pangaea Biotech, Quirón Dexeus University Hospital , Barcelona , Spain
| | - María José Catalán
- Laboratory of Oncology, Pangaea Biotech, Quirón Dexeus University Hospital , Barcelona , Spain
| | - Raquel Campos
- Laboratory of Oncology, Pangaea Biotech, Quirón Dexeus University Hospital , Barcelona , Spain
| | - Ana Pérez-Rosado
- Laboratory of Oncology, Pangaea Biotech, Quirón Dexeus University Hospital , Barcelona , Spain
| | - Jordi Bertran-Alamillo
- Laboratory of Oncology, Pangaea Biotech, Quirón Dexeus University Hospital , Barcelona , Spain
| | | | | | - María González-Cao
- Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital , Barcelona , Spain
| | - Xavier González
- Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital , Barcelona , Spain
| | | | - Santiago Viteri
- Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital , Barcelona , Spain
| | - Niki Karachaliou
- Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital , Barcelona , Spain
| | - Rafael Rosell
- Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain; Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Badalona, Spain
| |
Collapse
|
|
43
|
Oral Biofluid Biomarker Research: Current Status and Emerging Frontiers. Diagnostics (Basel) 2016; 6:diagnostics6040045. [PMID: 27999326 PMCID: PMC5192520 DOI: 10.3390/diagnostics6040045] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Revised: 11/15/2016] [Accepted: 12/07/2016] [Indexed: 12/24/2022] Open
Abstract
Salivary diagnostics is a rapidly advancing field that offers clinicians and patients the potential of rapid, noninvasive diagnostics with excellent accuracy. In order for the complete realization of the potential of saliva, however, extensive profiling of constituents must be conducted and diagnostic biomarkers must be thoroughly validated. This article briefly overviews the process of conducting a study of salivary biomarkers in a patient cohort and highlights the studies that have been conducted on different classes of molecules in the saliva. Emerging frontiers in salivary diagnostics research that may significantly advance the field will also be highlighted.
Collapse
|
|
44
|
Pérez-Callejo D, Romero A, Provencio M, Torrente M. Liquid biopsy based biomarkers in non-small cell lung cancer for diagnosis and treatment monitoring. Transl Lung Cancer Res 2016; 5:455-465. [PMID: 27826527 DOI: 10.21037/tlcr.2016.10.07] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Advances in the knowledge of the biology of non-small cell lung cancer (NSCLC) have revealed molecular information used for systemic cancer therapy targeting metastatic disease, with an important impact on patients overall survival (OS) and quality of life. However, a biopsy of overt metastases is an invasive procedure limited to certain locations and not easily acceptable in the clinic. Moreover, a single biopsy cannot reflect the clonal heterogeneity of the tumor. The analysis of peripheral blood samples of cancer patients represents a new source of cancer-derived material, known as liquid biopsy, and its components can be obtained from almost all body fluids. These components have shown to reflect characteristics of the status of both the primary and metastatic diseases, helping the clinicians to move towards a personalized medicine. The present review focuses on the liquid biopsy components: circulating tumor cells (CTCS), circulating free DNA (cfDNA), exosomes and tumor-educated platelets (TEP); the isolation technologies used and their potential use for non-invasive screening, early diagnosis, prognosis, response to treatment and real time monitoring of the disease, in NSCLC patients.
Collapse
Affiliation(s)
- David Pérez-Callejo
- Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain
| | - Atocha Romero
- Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain
| | - Mariano Provencio
- Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain
| | - María Torrente
- Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain
| |
Collapse
|
|
45
|
Mishra S, Saadat D, Kwon O, Lee Y, Choi WS, Kim JH, Yeo WH. Recent advances in salivary cancer diagnostics enabled by biosensors and bioelectronics. Biosens Bioelectron 2016; 81:181-197. [PMID: 26946257 DOI: 10.1016/j.bios.2016.02.040] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 02/12/2016] [Accepted: 02/14/2016] [Indexed: 01/05/2023]
Abstract
There is a high demand for a non-invasive, rapid, and highly accurate tool for disease diagnostics. Recently, saliva based diagnostics for the detection of specific biomarkers has drawn significant attention since the sample extraction is simple, cost-effective, and precise. Compared to blood, saliva contains a similar variety of DNA, RNA, proteins, metabolites, and microbiota that can be compiled into a multiplex of cancer detection markers. The salivary diagnostic method holds great potential for early-stage cancer diagnostics without any complicated and expensive procedures. Here, we review various cancer biomarkers in saliva and compare the biomarkers efficacy with traditional diagnostics and state-of-the-art bioelectronics. We summarize biomarkers in four major groups: genomics, transcriptomics, proteomics, and metabolomics/microbiota. Representative bioelectronic systems for each group are summarized based on various stages of a cancer. Systematic study of oxidative stress establishes the relationship between macromolecules and cancer biomarkers in saliva. We also introduce the most recent examples of salivary diagnostic electronics based on nanotechnologies that can offer rapid, yet highly accurate detection of biomarkers. A concluding section highlights areas of opportunity in the further development and applications of these technologies.
Collapse
Affiliation(s)
- Saswat Mishra
- Department of Mechanical and Nuclear Engineering, School of Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - Darius Saadat
- School of Engineering and Computer Science, Washington State University, Vancouver, WA 98686, USA
| | - Ohjin Kwon
- Department of Mechanical and Nuclear Engineering, School of Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - Yongkuk Lee
- Department of Mechanical and Nuclear Engineering, School of Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - Woon-Seop Choi
- School of Display Engineering, Hoseo University, Asan, Republic of Korea
| | - Jong-Hoon Kim
- School of Engineering and Computer Science, Washington State University, Vancouver, WA 98686, USA.
| | - Woon-Hong Yeo
- Department of Mechanical and Nuclear Engineering, School of Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA; Center for Rehabilitation Science and Engineering, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
| |
Collapse
|
|
46
|
Extracellular vesicles in breast cancer drug resistance and their clinical application. Tumour Biol 2016; 37:2849-61. [PMID: 26797784 DOI: 10.1007/s13277-015-4683-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 12/16/2015] [Indexed: 02/06/2023] Open
Abstract
Drug resistance currently represents a daunting challenge in the treatment of breast cancer patients. With an increased understanding of the underlying mechanisms of drug resistance, the role of extracellular vesicles (EVs) in the development of chemo-insensitivity attracts extensive attention. EVs are membrane-limited, cell type-dependent vesicles that are secreted by normal or malignant cells. EVs comprise various types of contents, including genetic cargoes, proteins, and specific lipids. The characteristics of the contents determine their specific functions in not only physiological but also pathological conditions. It has been demonstrated that miRNAs and proteins in EVs are strongly correlated with breast cancer drug resistance. Additionally, they may exert an influence on de novo and acquired resistance bioprocesses. With the advances in extraction and detection technologies, EVs have also been employed to precisely diagnose and predict the outcome of therapy in breast cancer. On the other hand, they can also be exploited as efficient delivery system in future anticancer applications. In this paper, we summarized relative mechanisms concerning the relationship between EVs and breast cancer drug resistance, and then, we provide up-to-date research advances in the clinical application of EVs.
Collapse
|
|
47
|
Müller G. Personalized Diagnosis and Therapy. DRUG DISCOVERY AND EVALUATION: PHARMACOLOGICAL ASSAYS 2016:3167-3284. [DOI: 10.1007/978-3-319-05392-9_152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
48
|
Zlotogorski-Hurvitz A, Dayan D, Chaushu G, Salo T, Vered M. Morphological and molecular features of oral fluid-derived exosomes: oral cancer patients versus healthy individuals. J Cancer Res Clin Oncol 2016; 142:101-10. [PMID: 26115960 DOI: 10.1007/s00432-015-2005-3] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2015] [Accepted: 06/15/2015] [Indexed: 11/29/2022]
Abstract
PURPOSE Oral cancer (OC) patients are at high risk to develop recurrent disease or secondary primary cancers with no available biomarkers to detect these events until a visible lesion is readily present and diagnosed by biopsy. Exosomes secreted by cancer cells are involved in tumor growth, invasion and metastasis. We aimed to determine morphological and molecular differences between oral fluid (OF)-derived exosomes of OC patients and those isolated from healthy individuals (HI). METHODS OF from OC patients (n = 36) and HI (n = 25) was initially assessed by nanoparticle tracking analysis (NTA). Following ultracentrifugation, exosomal pellets of OC patients and HI were morphologically examined by transmission electron microscopy and atomic force microscopy (AFM). Enzyme-linked immunosorbent assay (ELISA) and western blotting (WB) were used to analyze the expression of exosomal markers--CD9, CD81 and CD63. RESULTS NTA showed that OC samples of OF had a significantly higher concentration of nanoparticles/ml (p = 0.01) and modal nanoparticle size (p = 0.002) compared to HI. The difference in size was structurally highlighted by AFM three-dimensional images applied on exosomal pellets. ELISA and WB showed differential expression of exosomal markers in OC exosomes compared to HI: lower expression of CD81 and CD9 in contrast to a higher expression of CD63 (~53 kDa). CONCLUSIONS OF-derived exosomes from OC patients differ both morphologically and molecularly from exosomes present in HI. This study is a baseline that provides a starting point for finding exosomal biomarkers for early detection of malignant changes in high-risk patients without overt clinical signs/lesions.
Collapse
Affiliation(s)
- Ayelet Zlotogorski-Hurvitz
- Department of Oral Pathology and Oral Medicine, School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Dan Dayan
- Department of Oral Pathology and Oral Medicine, School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Gavriel Chaushu
- Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tel Aviv University and Department of Oral and Maxillofacial Surgery, Rabin Medical Center, Petah Tikva, Israel
| | - Tuula Salo
- Departments of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu and Oulu University Hospital, Oulu, Finland
- Medical Research Center, Oulu, Finland
- Institute of Dentistry, University of Helsinki, Helsinki, Finland
| | - Marilena Vered
- Department of Oral Pathology and Oral Medicine, School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel.
- Institute of Pathology, The Chaim Sheba Medical Center, Tel Hashomer, Israel.
| |
Collapse
|
|
49
|
Urinary Exosomes: The Potential for Biomarker Utility, Intercellular Signaling and Therapeutics in Urological Malignancy. J Urol 2015; 195:1331-1339. [PMID: 26714199 DOI: 10.1016/j.juro.2015.08.115] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/20/2015] [Indexed: 01/22/2023]
Abstract
PURPOSE Exosomes are small secreted vesicles that contain proteins, mRNA and miRNA with the potential to alter signaling pathways in recipient cells. While exosome research has flourished, few publications have specifically considered the role of genitourinary cancer shed exosomes in urine, their implication in disease progression and their usefulness as noninvasive biomarkers. In this review we examined the current literature on the role of exosomes in intercellular communication and as biomarkers, and their potential as delivery vehicles for therapeutic applications in bladder, prostate and renal cancer. MATERIALS AND METHODS We searched PubMed® and Google® with the key words prostate cancer, bladder cancer, kidney cancer, exosomes, microvesicles and urine. Relevant articles, including original research studies and reviews, were selected based on contents. A review of this literature was generated. RESULTS Cancer exosomes can be isolated from urine using various techniques. Cancer cells have been found to secrete more exosomes than normal cells. These exosomes have a role in cellular communication by interacting with and depositing their cargo in target cells. Bladder, prostate and renal cancer exosomes have been shown to enhance migration, invasion and angiogenesis. These exosomes have also been shown to increase proliferation, confer drug resistance and promote immune evasion. CONCLUSIONS Urinary exosomes can be isolated from bladder, kidney and prostate cancer. They serve as a potential reservoir for biomarker identification. Exosomes also have potential for therapeutics as siRNA or pharmacological agents can be loaded into exosomes.
Collapse
|
|
50
|
Les exosomes en pratique clinique : exemple du cancer bronchique. ONCOLOGIE 2015. [DOI: 10.1007/s10269-015-2545-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
|