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Shah KA, Ali T, Hussain Y, Dormocara A, You B, Cui JH. Isolation, characterization and therapeutic potentials of exosomes in lung cancer: Opportunities and challenges. Biochem Biophys Res Commun 2025; 759:151707. [PMID: 40153996 DOI: 10.1016/j.bbrc.2025.151707] [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: 12/06/2024] [Revised: 02/08/2025] [Accepted: 03/25/2025] [Indexed: 04/01/2025]
Abstract
Lung cancer (LC) signifies the primary cause of cancer-related mortality, representing 24 % of all cancer fatalities. LC is intricate and necessitates innovative approaches for early detection, precise diagnosis, and tailored treatment. Exosomes (EXOs), a subclass of extracellular vesicles (EVs), are integral to LC advancement, intercellular communication, tumor spread, and resistance to anticancer therapies. EXOs represent a viable drug delivery strategy owing to their distinctive biological characteristics, such as natural origin, biocompatibility, stability in blood circulation, minimal immunogenicity, and potential for modification. They can function as vehicles for targeted pharmaceuticals and facilitate the advancement of targeted therapeutics. EXOs are pivotal in the metastatic cascade, facilitating communication between cancer cells and augmenting their invasive capacity. Nonetheless, obstacles such as enhancing cargo loading efficiency, addressing homogeneity concerns during preparation, and facilitating large-scale clinical translation persist. Interdisciplinary collaboration in research is crucial for enhancing the efficacy of EXOs drug delivery systems. This review explores the role of EXOs in LC, their potential as therapeutic agents, and challenges in their development, aiming to advance targeted treatments. Future research should concentrate on engineering optimization and developing innovative EXOs to improve flexibility and effectiveness in clinical applications.
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Affiliation(s)
- Kiramat Ali Shah
- College of Pharmaceutical Science, Soochow University, Renai Road 199, SIP, 215213, Suzhou, Jiangsu, China
| | - Tariq Ali
- Department of Civil and Environmental Engineering, Shantou University, Shantou, Guangdong, 515063, China
| | - Yaseen Hussain
- College of Pharmaceutical Science, Soochow University, Renai Road 199, SIP, 215213, Suzhou, Jiangsu, China
| | - Amos Dormocara
- College of Pharmaceutical Science, Soochow University, Renai Road 199, SIP, 215213, Suzhou, Jiangsu, China
| | - Bengang You
- College of Pharmaceutical Science, Soochow University, Renai Road 199, SIP, 215213, Suzhou, Jiangsu, China
| | - Jing-Hao Cui
- College of Pharmaceutical Science, Soochow University, Renai Road 199, SIP, 215213, Suzhou, Jiangsu, China.
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2
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Phan N, Li Y, Yang M, Liu F. Tear fluid derived extracellular vesicles for new biomarker discovery. Ocul Surf 2025; 37:314-322. [PMID: 40368029 DOI: 10.1016/j.jtos.2025.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 04/23/2025] [Accepted: 05/05/2025] [Indexed: 05/16/2025]
Abstract
Various cell types release extracellular vesicles (EVs) containing proteins, DNA, and RNA essential for intercellular communication. The bioactive molecules from EVs can reflect disease status and monitor progression, while their communication abilities suggest therapeutic potential. We will review various EV isolation methods, EV-enriched fluids, and studies analyzing differential mi-RNA and protein levels extracted from EVs. Specifically, tear-derived EVs, which protect their molecular content and allow for real-time monitoring of ocular conditions such as Dry Eye Disease (DED), Sjögren's disease (SJD), Ocular graft-versus-host disease (oGVHD), and Diabetic Retinopathy (DR), which all currently remain undiagnosed in patients. EVs also provide potential as carriers for gene transfer, and mesenchymal stem cell (MSCs)-derived EVs are shown to be immunomodulatory, demonstrating promise for autoimmune ocular diseases. Through the multi-omic analysis of tear-fluid content, EVs are promising biomarkers and therapeutic agents in ocular diseases.
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Affiliation(s)
- Natalie Phan
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA; Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, 94720, USA
| | - Yi Li
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Menglu Yang
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA, 02114, USA.
| | - Fei Liu
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
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3
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Pons Royo MDC, Jungbauer A. Polyethylene glycol precipitation: fundamentals and recent advances. Prep Biochem Biotechnol 2025:1-20. [PMID: 40084924 DOI: 10.1080/10826068.2025.2470220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2025]
Abstract
Downstream processing continues to face significant bottlenecks due to current purification technologies and improvements in upstream. Chromatography systems have been the primary method for purification due to their high yields and purities. However, the use of high-titer-producing strains has highlighted limitations in chromatographic steps, including mass transfer limitations, low capacity, and scalability issues. These challenges, combined with the growing interest in fully continuous manufacturing processes, have led to a widespread interest in alternative to affinity chromatography systems. Polyethylene glycol precipitation has been demonstrated to be a powerful, flexible, easily scalable, and titer-independent methodology for purifying therapeutic proteins such as monoclonal antibodies, achieving yields and purities comparable to chromatography systems. Furthermore, it also holds great potential for simplifying the current purification processes of new modalities and overcome current bottlenecks in downstream processing. Herein, we discuss the latest advances in polyethylene glycol precipitation as a purification technology and explore its future research directions and potential applications.
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Affiliation(s)
| | - Alois Jungbauer
- Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria
- Austrian Centre of Industrial Biotechnology (ACIB), Vienna, Austria
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4
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Deng Q, Yao X, Fang S, Sun Y, Liu L, Li C, Li G, Guo Y, Liu J. Mast cell-mediated microRNA functioning in immune regulation and disease pathophysiology. Clin Exp Med 2025; 25:38. [PMID: 39812911 PMCID: PMC11735496 DOI: 10.1007/s10238-024-01554-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 12/28/2024] [Indexed: 01/16/2025]
Abstract
Upon stimulation and activation, mast cells (MCs) release soluble mediators, including histamine, proteases, and cytokines. These mediators are often stored within cytoplasmic granules in MCs and may be released in a granulated form. The secretion of cytokines and chemokines occurs within hours following activation, with the potential to result in chronic inflammation. In addition to their role in allergic inflammation, MCs are components of the tumor microenvironment (TME). MicroRNAs (miRNAs) are small RNA molecules that do not encode proteins, but regulate post-transcriptional gene expression by binding to the 3' non-coding regions of mRNAs. This plays a crucial role in the function of MC, including the key processes of MC proliferation, maturation, apoptosis, and activation. It has been demonstrated that miRNAs are also present in extracellular vesicles (EVs) secreted by MCs. EVs derived from MCs mediate intercellular communication by carrying miRNAs, affecting various diseases including allergic diseases, intestinal disorders, neuroinflammation, and tumors. These findings provide important insights into the therapeutic mechanisms and targets of miRNAs in MCs that affect diseases. This review discusses the relevance of miRNA production by MCs in regulating their own activity and the effect of miRNAs putatively produced by other cells in the control of MC activity and their participation in selected pathologies.
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Affiliation(s)
- Qiuping Deng
- Department of Clinical Laboratory, Chengdu Jinjiang Hospital for Women's and Children's Health, Chengdu, 610016, Sichuan, China
| | - Xiuju Yao
- Department of Clinical Laboratory, 363 Hospital, Chengdu, 610016, Sichuan, China
| | - Siyun Fang
- Department of Clinical Laboratory, Chengdu Jinjiang Hospital for Women's and Children's Health, Chengdu, 610016, Sichuan, China
| | - Yueshan Sun
- Medical Research Center, The Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, 610031, China
| | - Lei Liu
- Medical Research Center, The Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, 610031, China
| | - Chao Li
- Department of Clinical Laboratory, Chengdu Jinjiang Hospital for Women's and Children's Health, Chengdu, 610016, Sichuan, China
| | - Guangquan Li
- Department of Clinical Laboratory, 363 Hospital, Chengdu, 610016, Sichuan, China
| | - Yuanbiao Guo
- Medical Research Center, The Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, 610031, China.
| | - Jinbo Liu
- The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China.
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Rodríguez-Sanz J, Muñoz-González N, Cubero JP, Ordoñez P, Gil V, Langarita R, Ruiz M, Forner M, Marín-Oto M, Vera E, Baptista P, Polverino F, Domingo JA, García-Tirado J, Marin JM, Sanz-Rubio D. Peripheral Extracellular Vesicles for Diagnosis and Prognosis of Resectable Lung Cancer: The LUCEx Study Protocol. J Clin Med 2025; 14:411. [PMID: 39860417 PMCID: PMC11765880 DOI: 10.3390/jcm14020411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 12/27/2024] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Lung cancer is the primary cause of cancer-related deaths. Most patients are typically diagnosed at advanced stages. Low-dose computed tomography (LDCT) has been proven to reduce lung cancer mortality, but screening programs using LDCT are associated with a high number of false positives and unnecessary thoracotomies. It is therefore imperative that a certain diagnosis is refined, especially in cases of solitary pulmonary nodules that are difficult to technically access for an accurate preoperative diagnosis. Extracellular vesicles (EVs) involved in intercellular communication may be an innovative biomarker for diagnosis and therapeutic strategies in lung cancer, regarding their ability to carry tumor-specific cargo. The aim of the LUCEx study is to determine if extracellular vesicle cargoes from both lung tissue and blood could provide complementary information to screen lung cancer patients and enable personalized follow-up after the surgery. Methods: The LUCEx study is a prospective study aiming to recruit 600 patients with lung cancer and 50 control subjects (false positives) undergoing surgery after diagnostic imaging for suspected pulmonary nodules using computed tomography (CT) scans. These patients will undergo curative surgery at the Department of Thoracic Surgery of the Miguel Servet Hospital in Zaragoza, Spain, and will be followed-up for at least 5 years. At baseline, samples from both tumor distal lung tissue and preoperative peripheral blood will be collected and processed to compare the quantity and content of EVs, particularly their micro-RNA (miRNA) cargo. At the third and fifth years of follow-up, CT scans, functional respiratory tests, and blood extractions will be performed. Discussion: Extracellular vesicles and their miRNA have emerged as promising tools for the diagnosis and prognosis of several diseases, including cancer. The LUCEx study, based on an observational clinical cohort, aims to understand the role of these vesicles and their translational potential as complementary tools for imaging diagnosis and prognosis.
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Affiliation(s)
- Jorge Rodríguez-Sanz
- Pulmonology and Critical Care Unit, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
- Translational Research Unit, Hospital Universitario Miguel Servet, IIS Aragón, 50009 Zaragoza, Spain
- CIBER Enfermedades Respiratorias, 28029 Madrid, Spain
| | - Nadia Muñoz-González
- Translational Research Unit, Hospital Universitario Miguel Servet, IIS Aragón, 50009 Zaragoza, Spain
- CIBER Enfermedades Respiratorias, 28029 Madrid, Spain
- Thoracic Surgery Unit, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
| | - José Pablo Cubero
- Translational Research Unit, Hospital Universitario Miguel Servet, IIS Aragón, 50009 Zaragoza, Spain
- CIBER Enfermedades Respiratorias, 28029 Madrid, Spain
| | - Pablo Ordoñez
- Thoracic Surgery Unit, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
| | - Victoria Gil
- Translational Research Unit, Hospital Universitario Miguel Servet, IIS Aragón, 50009 Zaragoza, Spain
- CIBER Enfermedades Respiratorias, 28029 Madrid, Spain
| | - Raquel Langarita
- Translational Research Unit, Hospital Universitario Miguel Servet, IIS Aragón, 50009 Zaragoza, Spain
- CIBER Enfermedades Respiratorias, 28029 Madrid, Spain
| | - Myriam Ruiz
- Translational Research Unit, Hospital Universitario Miguel Servet, IIS Aragón, 50009 Zaragoza, Spain
- CIBER Enfermedades Respiratorias, 28029 Madrid, Spain
| | - Marta Forner
- Translational Research Unit, Hospital Universitario Miguel Servet, IIS Aragón, 50009 Zaragoza, Spain
- CIBER Enfermedades Respiratorias, 28029 Madrid, Spain
| | - Marta Marín-Oto
- Translational Research Unit, Hospital Universitario Miguel Servet, IIS Aragón, 50009 Zaragoza, Spain
- CIBER Enfermedades Respiratorias, 28029 Madrid, Spain
| | - Elisabet Vera
- Pulmonology and Critical Care Unit, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
| | - Pedro Baptista
- Instituto de Investigación Sanitaria de Aragón (IIS Aragón), 50009 Zaragoza, Spain
| | - Francesca Polverino
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Juan Antonio Domingo
- Pulmonology and Critical Care Unit, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
| | - Javier García-Tirado
- Thoracic Surgery Unit, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
| | - José María Marin
- Pulmonology and Critical Care Unit, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
- Translational Research Unit, Hospital Universitario Miguel Servet, IIS Aragón, 50009 Zaragoza, Spain
- CIBER Enfermedades Respiratorias, 28029 Madrid, Spain
| | - David Sanz-Rubio
- Translational Research Unit, Hospital Universitario Miguel Servet, IIS Aragón, 50009 Zaragoza, Spain
- CIBER Enfermedades Respiratorias, 28029 Madrid, Spain
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Wei Y, Hu X, Yuan S, Zhao Y, Zhu C, Guo M, Cui H. Identification of plasma exosomal lncRNA as a biomarker for early diagnosis of gastric cancer. Front Genet 2024; 15:1425591. [PMID: 39440243 PMCID: PMC11493672 DOI: 10.3389/fgene.2024.1425591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 09/23/2024] [Indexed: 10/25/2024] Open
Abstract
Background There were about 1,090,000 gastric cancer (GC) cases in 2020 in China. The incidence and mortality rates ranked the fifth and third among all kinds of cancers in China. Early diagnosis plays an important role in the treatment and prognosis of gastric cancer. In recent years, noninvasive diagnosis, especially plasma exosome lncRNAs, has become a promissing biomarkers with high specificity and sensitivity for early diagnosis of cancers. Methods In this study, plasma exosomes of patients with early gastric cancer were extracted efficiently by affinity membrane separation technology, including affinity adsorption, elution, affinity membrane regeneration and other steps. After identified by electron microscopy observation, particle size analysis and Western blot verification, the lncRNAs in the exosomes were extracted and were analysized by high-throughput RNA sequencing (RNA-Seq). The differentially expressed lncRNAs were verified by RT-qPCR in 93 patients with early gastric cancer and 49 normal controls. Results Electron microscopy, particle size analysis and Western blot showed that exosomes were successfully isolated from plasma. RNA-Seq results show that 76 lncRNAs were upregulated and 260 lncRNAs were downregulated in plasma exosomes of early gastric cancer patients compared with normal controls. RT-qPCR analysis indicated that a total of 6 lncRNAs were significantly and differentially expressed in gastric cancer patients compared to normal controls, with 2 (lncmstrg. 1319590, Lncmstrg. 2312697) highly expressed and 4 lowly expressed (lncmstr-g.1004024.1, lncmstrg. 2441832.8, lncmstrg. 315376.1, lncmstrg.907985.2,) (p < 0.05). The survival curve analysis indicated that lncmstrg.2441832.8 and lncmstrg.2312697 had higher sensitivity and specificity for the diagnosis of gastric cancer, respectively and AUC curve areas were 0.6211 and 0.631, p < 0.05, respectively, which were greater than the traditional clinical detection indexes CEA (0.61) and AFP (0.57). When combined lncmstrg.2441832.8 and lncmstrg.2312697 in gastric cancer diagnosis, AUC curve area reached 0.73, which was greater than CA199 (0.71). Conclusion Lncmstrg.2441832.8 and lncmstrg.2312697 may be a potential and promissing biomarkers for early diagnosis of gastric cancer.
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Affiliation(s)
- Ye Wei
- College of Medicine, Yangzhou University, Yangzhou, China
| | - Xuming Hu
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Shuai Yuan
- Yangzhou center for disease control and prevention, Yangzhou, China
| | - Yue Zhao
- Department of Medical Affaires, Yangzhou Maternity and Child Health Hospital, Yangzhou, China
| | - Chunhui Zhu
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Mingzhou Guo
- Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China
| | - Hengmi Cui
- College of Medicine, Yangzhou University, Yangzhou, China
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, Yangzhou, China
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7
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Khan A, Raza F, He N. Nanoscale Extracellular Vesicle-Enabled Liquid Biopsy: Advances and Challenges for Lung Cancer Detection. MICROMACHINES 2024; 15:1181. [PMID: 39459055 PMCID: PMC11509190 DOI: 10.3390/mi15101181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 09/20/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024]
Abstract
Lung cancer is responsible for the death of over a million people worldwide every year. With its high mortality rate and exponentially growing number of new cases, lung cancer is a major threat to public health. The high mortality and poor survival rates of lung cancer patients can be attributed to its stealth progression and late diagnosis. For a long time, intrusive tissue biopsy has been considered the gold standard for lung cancer diagnosis and subtyping; however, the intrinsic limitations of tissue biopsy cannot be overlooked. In addition to being invasive and costly, it also suffers from limitations in sensitivity and specificity, is not suitable for repeated sampling, provides restricted information about the tumor and its molecular landscape, and is inaccessible in several cases. To cope with this, advancements in diagnostic technologies, such as liquid biopsy, have shown great prospects. Liquid biopsy is an innovative non-invasive approach in which cancer-related components called biomarkers are detected in body fluids, such as blood, urine, saliva and others. It offers a less invasive alternative with the potential for applications such as routine screening, predicting treatment outcomes, evaluating treatment effectiveness, detecting residual disease, or disease recurrence. A large number of research articles have indicated extracellular vesicles (EVs) as ideal biomarkers for liquid biopsy. EVs are a heterogeneous collection of membranous nanoparticles with diverse sizes, contents, and surface markers. EVs play a critical role in pathophysiological states and have gained prominence as diagnostic and prognostic biomarkers for multiple diseases, including lung cancer. In this review, we provide a detailed overview of the potential of EV-based liquid biopsy for lung cancer. Moreover, it highlights the strengths and weaknesses of various contemporary techniques for EV isolation and analysis in addition to the challenges that need to be addressed to ensure the widespread clinical application of EV-based liquid biopsies for lung cancer. In summary, EV-based liquid biopsies present interesting opportunities for the development of novel diagnostic and prognostic platforms for lung cancer, one of the most abundant cancers responsible for millions of cancer-related deaths worldwide.
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Affiliation(s)
- Adeel Khan
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, National Demonstration Center for Experimental Biomedical Engineering Education, Southeast University, Nanjing 210096, China
| | - Faisal Raza
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China;
| | - Nongyue He
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, National Demonstration Center for Experimental Biomedical Engineering Education, Southeast University, Nanjing 210096, China
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Hassanin AAI, Ramos KS. Circulating Exosomal miRNA Profiles in Non-Small Cell Lung Cancers. Cells 2024; 13:1562. [PMID: 39329746 PMCID: PMC11430728 DOI: 10.3390/cells13181562] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 09/08/2024] [Accepted: 09/15/2024] [Indexed: 09/28/2024] Open
Abstract
A growing number of studies have shown that microRNAs (miRNAs) can exert oncogenic or tumor suppressor activities in a variety of cancers, including lung cancer. Given their presence in exosome preparations, microRNA molecules may in fact participate in exosomal intercellular transfers and signaling. In the present study, we examined the profile of 25 circulating exosomal microRNAs in ostensibly healthy controls compared to patients with squamous cell lung cancers (SQCLC) or lung adenocarcinomas (LUAD). Eight miRNAs, namely, miR-21-5p, miR-126-3p, miR-210-3p, miR-221-3p, Let-7b-5p, miR-146a-5p, miR-222-3p, and miR-9-5p, were highly enriched in the cohort and selected for further analyses. All miRNAs were readily detected in non-small cell lung cancer (NSCLC) patients of both sexes at all cancer stages, and their levels in exosomes correlated with the clinicopathological characteristics of tumors. Thus, the presence of these miRNAs in circulating exosomes may contribute to the regulation of oncogenic activity in patients with NSCLC.
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Affiliation(s)
- Abeer A. I. Hassanin
- Center for Genomic and Precision Medicine, Texas A&M Institute of Biosciences and Technology, Texas Medical Center, Houston, TX 77030, USA;
- Department of Animal Wealth Development, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Kenneth S. Ramos
- Center for Genomic and Precision Medicine, Texas A&M Institute of Biosciences and Technology, Texas Medical Center, Houston, TX 77030, USA;
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Oh HJ, Imam-Aliagan AB, Kim YB, Kim HJ, Izaguirre IA, Sung CK, Yim H. Clinical applications of circulating biomarkers in non-small cell lung cancer. Front Cell Dev Biol 2024; 12:1449232. [PMID: 39239557 PMCID: PMC11375801 DOI: 10.3389/fcell.2024.1449232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 08/12/2024] [Indexed: 09/07/2024] Open
Abstract
Despite recent advances in cancer diagnostics and treatment, the mortality associated with lung cancer is still the highest in the world. Late-stage diagnosis, often accompanied by metastasis, is a major contributor to the high mortality rates, emphasizing the urgent need for reliable and readily accessible diagnostic tools that can detect biomarkers unique to lung cancer. Circulating factors, such as circulating tumor DNA and extracellular vesicles, from liquid biopsy have been recognized as diagnostic or prognostic markers in lung cancer. Numerous clinical studies are currently underway to investigate the potential of circulating tumor DNA, circulating tumor RNA, exosomes, and exosomal microRNA within the context of lung cancer. Those clinical studies aim to address the poor diagnostics and limited treatment options for lung cancer, with the ultimate goal of developing clinical markers and personalized therapies. In this review, we discuss the roles of each circulating factor, its current research status, and ongoing clinical studies of circulating factors in non-small cell lung cancer. Additionally, we discuss the circulating factors specifically found in lung cancer stem cells and examine approved diagnostic assays designed to detect circulating biomarkers in lung cancer patients.
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Affiliation(s)
- Hyun-Ji Oh
- Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do, Republic of Korea
| | - Abdulhamid B Imam-Aliagan
- Department of Biological and Health Sciences, College of Arts and Sciences, Texas A&M University-Kingsville, Kingsville, TX, United States
| | - Yeo-Bin Kim
- Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do, Republic of Korea
| | - Hyun-Jin Kim
- Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do, Republic of Korea
| | - Issac A Izaguirre
- Department of Biological and Health Sciences, College of Arts and Sciences, Texas A&M University-Kingsville, Kingsville, TX, United States
| | - Chang K Sung
- Department of Biological and Health Sciences, College of Arts and Sciences, Texas A&M University-Kingsville, Kingsville, TX, United States
| | - Hyungshin Yim
- Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do, Republic of Korea
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10
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Song J, Zhou D, Cui L, Wu C, Jia L, Wang M, Li J, Ya J, Ji X, Meng R. Advancing stroke therapy: innovative approaches with stem cell-derived extracellular vesicles. Cell Commun Signal 2024; 22:369. [PMID: 39039539 PMCID: PMC11265156 DOI: 10.1186/s12964-024-01752-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 07/16/2024] [Indexed: 07/24/2024] Open
Abstract
Stroke is a leading cause of mortality and long-term disability globally, with acute ischemic stroke (AIS) being the most common subtype. Despite significant advances in reperfusion therapies, their limited time window and associated risks underscore the necessity for novel treatment strategies. Stem cell-derived extracellular vesicles (EVs) have emerged as a promising therapeutic approach due to their ability to modulate the post-stroke microenvironment and facilitate neuroprotection and neurorestoration. This review synthesizes current research on the therapeutic potential of stem cell-derived EVs in AIS, focusing on their origin, biogenesis, mechanisms of action, and strategies for enhancing their targeting capacity and therapeutic efficacy. Additionally, we explore innovative combination therapies and discuss both the challenges and prospects of EV-based treatments. Our findings reveal that stem cell-derived EVs exhibit diverse therapeutic effects in AIS, such as promoting neuronal survival, diminishing neuroinflammation, protecting the blood-brain barrier, and enhancing angiogenesis and neurogenesis. Various strategies, including targeting modifications and cargo modifications, have been developed to improve the efficacy of EVs. Combining EVs with other treatments, such as reperfusion therapy, stem cell transplantation, nanomedicine, and gut microbiome modulation, holds great promise for improving stroke outcomes. However, challenges such as the heterogeneity of EVs and the need for standardized protocols for EV production and quality control remain to be addressed. Stem cell-derived EVs represent a novel therapeutic avenue for AIS, offering the potential to address the limitations of current treatments. Further research is needed to optimize EV-based therapies and translate their benefits to clinical practice, with an emphasis on ensuring safety, overcoming regulatory hurdles, and enhancing the specificity and efficacy of EV delivery to target tissues.
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Affiliation(s)
- Jiahao Song
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Da Zhou
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China.
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
| | - Lili Cui
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Chuanjie Wu
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Lina Jia
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Mengqi Wang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Jingrun Li
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Jingyuan Ya
- Academic Unit of Mental Health and Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, England
| | - Xunming Ji
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Ran Meng
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China.
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
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11
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Skoczylas Ł, Gawin M, Fochtman D, Widłak P, Whiteside TL, Pietrowska M. Immune capture and protein profiling of small extracellular vesicles from human plasma. Proteomics 2024; 24:e2300180. [PMID: 37713108 PMCID: PMC11046486 DOI: 10.1002/pmic.202300180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 08/11/2023] [Accepted: 08/14/2023] [Indexed: 09/16/2023]
Abstract
Extracellular vesicles (EVs), the key players in inter-cellular communication, are produced by all cell types and are present in all body fluids. Analysis of the proteome content is an important approach in structural and functional studies of these vesicles. EVs circulating in human plasma are heterogeneous in size, cellular origin, and functions. This heterogeneity and the potential presence of contamination with plasma components such as lipoprotein particles and soluble plasma proteins represent a challenge in profiling the proteome of EV subsets by mass spectrometry. An immunocapture strategy prior to mass spectrometry may be used to isolate a homogeneous subpopulation of small EVs (sEV) with a specific endocytic origin from plasma or other biofluids. Immunocapture selectively separates EV subpopulations in biofluids based on the presence of a unique protein carried on the vesicle surface. The advantages and disadvantages of EV immune capture as a preparative step for mass spectrometry are discussed.
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Affiliation(s)
- Łukasz Skoczylas
- Maria Sklodowska-Curie National Research Institute of Oncology, 44-102 Gliwice, Poland
| | - Marta Gawin
- Maria Sklodowska-Curie National Research Institute of Oncology, 44-102 Gliwice, Poland
| | - Daniel Fochtman
- Maria Sklodowska-Curie National Research Institute of Oncology, 44-102 Gliwice, Poland
- Silesian University of Technology, 44-100 Gliwice, Poland
| | - Piotr Widłak
- Medical University of Gdańsk, 80-210 Gdańsk, Poland
| | - Theresa L. Whiteside
- UPMC Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Monika Pietrowska
- Maria Sklodowska-Curie National Research Institute of Oncology, 44-102 Gliwice, Poland
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12
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Zhou Y, Tao L, Qiu J, Xu J, Yang X, Zhang Y, Tian X, Guan X, Cen X, Zhao Y. Tumor biomarkers for diagnosis, prognosis and targeted therapy. Signal Transduct Target Ther 2024; 9:132. [PMID: 38763973 PMCID: PMC11102923 DOI: 10.1038/s41392-024-01823-2] [Citation(s) in RCA: 128] [Impact Index Per Article: 128.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 03/07/2024] [Accepted: 04/02/2024] [Indexed: 05/21/2024] Open
Abstract
Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.
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Affiliation(s)
- Yue Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lei Tao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiahao Qiu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinyu Yang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Yu Zhang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
- School of Medicine, Tibet University, Lhasa, 850000, China
| | - Xinyu Tian
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinqi Guan
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaobo Cen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yinglan Zhao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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13
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Song DH, Lee JS, Lee JH, Kim DC, Yang JW, Kim MH, Na JM, Cho HK, Yoo J, An HJ. Exosome-mediated secretion of miR-127-3p regulated by RAB27A accelerates metastasis in renal cell carcinoma. Cancer Cell Int 2024; 24:153. [PMID: 38685086 PMCID: PMC11057152 DOI: 10.1186/s12935-024-03334-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 04/18/2024] [Indexed: 05/02/2024] Open
Abstract
BACKGROUND The exosome-mediated extracellular secretion of miRNAs occurs in many cancers, and RAB27A is a potent regulator of exosome secretion. For metastatic renal cell carcinoma (RCC), this study examines the mechanisms of cancer metastasis via the RAB27A-regulated secretion of specific miRNAs. METHODS RAB27A knockdown (KD) and overexpressing (OE) RCC cells were used to examine cell migration and adhesion. The particle counts and sizes of exosomes in RAB27A OE cells were analyzed using Exoview, and those of intraluminal vesicles (ILV) and multivesicular bodies (MVB) were measured using an electron microscope. Analysis of RNA sequences, protein-protein interaction networks, and the competing endogenous RNA (ceRNA) network were used to identify representative downregulated miRNAs that are likely to undergo cargo-sorting into exosomes and subsequent secretion. A molecular beacon of miR-137-3p, one of the most representatively downregulated genes with a fold change of 339, was produced, and its secretion was analyzed using Exoview. RAB27A OE and control cells were incubated in an exosome-containing media to determine the uptake of tumor suppressor miRNAs that affect cancer cell metastasis. RESULTS Migration and cell adhesion were higher in RAB27A OE cells than in RAB27A KD cells. Electron microscopy revealed that the numbers of multivesicular bodies and intraluminal vesicles per cell were higher in RAB27A OE cells than in control cells, suggesting their secretion. The finding revealed that miR-127-3p was sorted into exosomes and disposed of extracellularly. Protein-protein interaction analysis revealed MYCN to be the most significant hub for RAB27A-OE RCC cells. ceRNA network analysis revealed that MAPK4 interacted strongly with miR-127-3p. CONCLUSION The disposal of miR-127-3p through exosome secretion in RAB27A overexpressing cells may not inhibit the MAPK pathway to gain metastatic potential by activating MYCN. The exosomes containing miRNAs are valuable therapeutic targets for cancer treatment.
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Affiliation(s)
- Dae Hyun Song
- Department of Pathology, Gyeongsang National University Changwon Hospital, Changwon, South Korea
- Institute of Medical Sciences, Gyeongsang National University, Jinju, South Korea
- Department of Pathology, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Jong Sil Lee
- Institute of Medical Sciences, Gyeongsang National University, Jinju, South Korea
- Department of Pathology, Gyeongsang National University School of Medicine, Jinju, South Korea
- Department of Pathology, Gyeongsang National University Hospital, Jinju, South Korea
| | - Jeong-Hee Lee
- Institute of Medical Sciences, Gyeongsang National University, Jinju, South Korea
- Department of Pathology, Gyeongsang National University School of Medicine, Jinju, South Korea
- Department of Pathology, Gyeongsang National University Hospital, Jinju, South Korea
| | - Dong Chul Kim
- Institute of Medical Sciences, Gyeongsang National University, Jinju, South Korea
- Department of Pathology, Gyeongsang National University School of Medicine, Jinju, South Korea
- Department of Pathology, Gyeongsang National University Hospital, Jinju, South Korea
| | - Jung Wook Yang
- Institute of Medical Sciences, Gyeongsang National University, Jinju, South Korea
- Department of Pathology, Gyeongsang National University School of Medicine, Jinju, South Korea
- Department of Pathology, Gyeongsang National University Hospital, Jinju, South Korea
| | - Min Hye Kim
- Department of Pathology, Gyeongsang National University Hospital, Jinju, South Korea
| | - Ji Min Na
- Department of Pathology, Gyeongsang National University Hospital, Jinju, South Korea
| | - Hyun-Kyung Cho
- Institute of Medical Sciences, Gyeongsang National University, Jinju, South Korea
- Department of Ophthalmology, Gyeongsang National University Changwon Hospital, Gyeongsang National University, School of Medicine, Changwon, South Korea
| | - Jiyun Yoo
- Division of Applied Life Science (BK21 Plus) and Research Institute of Life Sciences, Gyeongsang National University, Jinju, South Korea
| | - Hyo Jung An
- Department of Pathology, Gyeongsang National University Changwon Hospital, Changwon, South Korea.
- Institute of Medical Sciences, Gyeongsang National University, Jinju, South Korea.
- Department of Pathology, Gyeongsang National University School of Medicine, Jinju, South Korea.
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14
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Han J, Jung JH, Lee SY, Park JH. Nanoplasmonic Detection of EGFR Mutations Based on Extracellular Vesicle-Derived EGFR-Drug Interaction. ACS APPLIED MATERIALS & INTERFACES 2024; 16:8266-8274. [PMID: 38335730 DOI: 10.1021/acsami.3c14907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/12/2024]
Abstract
Analysis of membrane proteins from extracellular vesicles (EVs) has emerged as an important strategy for molecular cancer diagnosis. The epidermal growth factor receptor (EGFR) is one of the most well-known oncogenic membrane proteins, particularly in non-small cell lung cancer (NSCLC), where targeted therapies using tyrosine kinase inhibitors (TKIs) are often addressed based on EGFR mutation status. Consequently, several studies aimed at analyzing oncogenic membrane proteins have been proposed for cancer diagnosis. However, conventional protein analysis still faces limitations due to the requirement for large sample quantities and extensive post-labeling processes. Here, we develop a nanoplasmonic detection method for EGFR mutations in the diagnosis of NSCLC based on interactions between EGFR loaded in EVs and TKI. Gefitinib is selected as a model TKI due to its strong signals in the surface-enhanced Raman spectroscopy (SERS) and mutation-dependent binding affinity to EGFR. We demonstrate an SERS signal attributed to gefitinib at a higher value in the EGFR exon 19 deletion, both in cells and EVs, compared to wild-type and exon 19 deletion/T790M variants. Furthermore, we observe a significantly higher gefitinib SERS signal in EGFR obtained from exon 19 deletion NSCLC patient plasma-derived EVs compared with those from wild-type and exon 19 deletion/T790M EVs. Since our approach utilizes an analysis of the SERS signal generated by the interaction between oncogenic membrane proteins within EVs and targeted drugs, its diagnostic applicability could potentially extend to other liquid biopsy methods based on EVs.
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Affiliation(s)
- Junhee Han
- Department of Bio and Brain Engineering and KAIST Institute for Health Science and Technology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Jik-Han Jung
- Department of Bio and Brain Engineering and KAIST Institute for Health Science and Technology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Sung Yong Lee
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul 08308, Republic of Korea
| | - Ji-Ho Park
- Department of Bio and Brain Engineering and KAIST Institute for Health Science and Technology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
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15
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Wen J, Yu JZ, Liu C, Ould Ismail AAO, Ma W. Exploring the Molecular Tumor Microenvironment and Translational Biomarkers in Brain Metastases of Non-Small-Cell Lung Cancer. Int J Mol Sci 2024; 25:2044. [PMID: 38396722 PMCID: PMC10889194 DOI: 10.3390/ijms25042044] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 01/17/2024] [Accepted: 02/01/2024] [Indexed: 02/25/2024] Open
Abstract
Brain metastases represent a significant clinical challenge in the treatment of non-small-cell lung cancer (NSCLC), often leading to a severe decline in patient prognosis and survival. Recent advances in imaging and systemic treatments have increased the detection rates of brain metastases, yet clinical outcomes remain dismal due to the complexity of the metastatic tumor microenvironment (TME) and the lack of specific biomarkers for early detection and targeted therapy. The intricate interplay between NSCLC tumor cells and the surrounding TME in brain metastases is pivotal, influencing tumor progression, immune evasion, and response to therapy. This underscores the necessity for a deeper understanding of the molecular underpinnings of brain metastases, tumor microenvironment, and the identification of actionable biomarkers that can inform multimodal treatment approaches. The goal of this review is to synthesize current insights into the TME and elucidate molecular mechanisms in NSCLC brain metastases. Furthermore, we will explore the promising horizon of emerging biomarkers, both tissue- and liquid-based, that hold the potential to radically transform the treatment strategies and the enhancement of patient outcomes.
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Affiliation(s)
- Jiexi Wen
- Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA
| | - Jie-Zeng Yu
- Division of Hematology/Oncology, Department of Medicine, University of California at San Francisco, San Francisco, CA 94143, USA
| | - Catherine Liu
- School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
| | - A. Aziz O. Ould Ismail
- Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA
| | - Weijie Ma
- Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA
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16
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Ye L, Chu X, Ni J, Chu L, Yang X, Zhu Z. NGS-based Tissue-Blood TMB Comparison and Blood-TMB Monitoring in Stage-III Non-Small Cell Lung Cancer Treated with Concurrent Chemoradiotherapy. Cancer Invest 2024; 42:165-175. [PMID: 38390854 DOI: 10.1080/07357907.2024.2316297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 02/05/2024] [Indexed: 02/24/2024]
Abstract
In this study, we analyzed the blood-based TMB (b-TMB) and its dynamic changes in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who received concurrent chemoradiotherapy. Baseline tissue and blood TMB from 15 patients showed a strong positive correlation (Pearson correlation = 0.937), and nearly all mutations were markedly reduced in the later course of treatment, indicating a treatment-related response. This study suggests that in patients with LA-NSCLC, b-TMB is a reliable biomarker, and its dynamic monitoring can help distinguish patients who might benefit most from the consolidated immunotherapy.
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Affiliation(s)
- Luxi Ye
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiao Chu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jianjiao Ni
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Li Chu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xi Yang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhengfei Zhu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Thoracic Oncology, Fudan University, Shanghai, China
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17
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Zhang C, Qin C, Dewanjee S, Bhattacharya H, Chakraborty P, Jha NK, Gangopadhyay M, Jha SK, Liu Q. Tumor-derived small extracellular vesicles in cancer invasion and metastasis: molecular mechanisms, and clinical significance. Mol Cancer 2024; 23:18. [PMID: 38243280 PMCID: PMC10797874 DOI: 10.1186/s12943-024-01932-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 01/02/2024] [Indexed: 01/21/2024] Open
Abstract
The production and release of tumor-derived small extracellular vesicles (TDSEVs) from cancerous cells play a pivotal role in the propagation of cancer, through genetic and biological communication with healthy cells. TDSEVs are known to orchestrate the invasion-metastasis cascade via diverse pathways. Regulation of early metastasis processes, pre-metastatic niche formation, immune system regulation, angiogenesis initiation, extracellular matrix (ECM) remodeling, immune modulation, and epithelial-mesenchymal transition (EMT) are among the pathways regulated by TDSEVs. MicroRNAs (miRs) carried within TDSEVs play a pivotal role as a double-edged sword and can either promote metastasis or inhibit cancer progression. TDSEVs can serve as excellent markers for early detection of tumors, and tumor metastases. From a therapeutic point of view, the risk of cancer metastasis may be reduced by limiting the production of TDSEVs from tumor cells. On the other hand, TDSEVs represent a promising approach for in vivo delivery of therapeutic cargo to tumor cells. The present review article discusses the recent developments and the current views of TDSEVs in the field of cancer research and clinical applications.
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Affiliation(s)
- Chi Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China
- The Institute of Skull Base Surgery and Neuro-Oncology at Hunan Province, Changsha, 410008, China
| | - Chaoying Qin
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China
- The Institute of Skull Base Surgery and Neuro-Oncology at Hunan Province, Changsha, 410008, China
| | - Saikat Dewanjee
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, West Bengal, India.
| | - Hiranmoy Bhattacharya
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, West Bengal, India
| | - Pratik Chakraborty
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, West Bengal, India
| | - Niraj Kumar Jha
- Centre of Research Impact and Outreach, Chitkara University Institute of Engineering and Technology, Chitkara University, Punjab, India
- Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun, 248007, India
| | - Moumita Gangopadhyay
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Barasat, Kolkata, 700126, West Bengal, India
| | - Saurabh Kumar Jha
- Department of Zoology, Kalindi College, University of Delhi, New Delhi, Delhi, 110008, India.
| | - Qing Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
- The Institute of Skull Base Surgery and Neuro-Oncology at Hunan Province, Changsha, 410008, China.
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18
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Rahimian S, Najafi H, Afzali B, Doroudian M. Extracellular Vesicles and Exosomes: Novel Insights and Perspectives on Lung Cancer from Early Detection to Targeted Treatment. Biomedicines 2024; 12:123. [PMID: 38255228 PMCID: PMC10813125 DOI: 10.3390/biomedicines12010123] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/24/2023] [Accepted: 01/04/2024] [Indexed: 01/24/2024] Open
Abstract
Lung cancer demands innovative approaches for early detection and targeted treatment. In addressing this urgent need, exosomes play a pivotal role in revolutionizing both the early detection and targeted treatment of lung cancer. Their remarkable capacity to encapsulate a diverse range of biomolecules, traverse biological barriers, and be engineered with specific targeting molecules makes them highly promising for both diagnostic markers and precise drug delivery to cancer cells. Furthermore, an in-depth analysis of exosomal content and biogenesis offers crucial insights into the molecular profile of lung tumors. This knowledge holds significant potential for the development of targeted therapies and innovative diagnostic strategies for cancer. Despite notable progress in this field, challenges in standardization and cargo loading persist. Collaborative research efforts are imperative to maximize the potential of exosomes and advance the field of precision medicine for the benefit of lung cancer patients.
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Affiliation(s)
| | | | | | - Mohammad Doroudian
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran 14911-15719, Iran; (S.R.); (H.N.); (B.A.)
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19
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Guo ZY, Tang Y, Cheng YC. Exosomes as Targeted Delivery Drug System: Advances in Exosome Loading, Surface Functionalization and Potential for Clinical Application. Curr Drug Deliv 2024; 21:473-487. [PMID: 35702803 DOI: 10.2174/1567201819666220613150814] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 04/13/2022] [Accepted: 04/22/2022] [Indexed: 11/22/2022]
Abstract
Exosomes are subtypes of vesicles secreted by almost all cells and can play an important role in intercellular communication. They contain various proteins, lipids, nucleic acids and other natural substances from their metrocytes. Exosomes are expected to be a new generation of drug delivery systems due to their low immunogenicity, high potential to transfer bioactive substances and biocompatibility. However, exosomes themselves are not highly targeted, it is necessary to develop new surface modification techniques and targeted drug delivery strategies, which are the focus of drug delivery research. In this review, we introduced the biogenesis of exosomes and their role in intercellular communication. We listed various advanced exosome drug-loading techniques. Emphatically, we summarized different exosome surface modification techniques and targeted drug delivery strategies. In addition, we discussed the application of exosomes in vaccines and briefly introduced milk exosomes. Finally, we clarified the clinical application prospects and shortcomings of exosomes.
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Affiliation(s)
- Zun Y Guo
- Department of Pharmacy, China Pharmaceutical University, No.639, Longmian Avenue, Nanjing 211198, P.R. China
| | - Yue Tang
- Department of Pharmacy, China Pharmaceutical University, No.639, Longmian Avenue, Nanjing 211198, P.R. China
| | - Yi C Cheng
- Department of Pharmacy, China Pharmaceutical University, No.639, Longmian Avenue, Nanjing 211198, P.R. China
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20
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Co EL, Hameed M, Sebastian SA, Garg T, Sudan S, Bheemisetty N, Mohan B. Narrative Review of Probiotic Use on the Recovery of Postoperative Patients with Esophageal Cancer. Curr Nutr Rep 2023; 12:635-642. [PMID: 37605086 DOI: 10.1007/s13668-023-00490-z] [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] [Accepted: 08/08/2023] [Indexed: 08/23/2023]
Abstract
PURPOSE OF REVIEW This narrative review discusses the significance of probiotic therapy in the postoperative care of patients with esophageal cancer and its role as an adjunct therapy to other treatment modalities for esophageal cancer. RECENT FINDINGS As such, there is an emerging need to address any malnutrition and gastrointestinal problems occurring in these patients which tend to have a strong negative impact on their prognosis. Probiotic effects on esophageal cancer biomarkers suggest that there is a positive correlation between these two factors. However, the beneficial effects remain controversial and warrant further investigation. Probiotics, now being widely utilized as postoperative therapy in some carcinomas of the gastrointestinal tract such as gastric cancer and colorectal cancer, have been shown in some clinical studies to positively impact the nutritional status of patients with esophageal cancer. Postoperative care among patients suffering from esophageal cancer is a very crucial aspect in the survival of these patients.
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Affiliation(s)
- Edzel Lorraine Co
- University of Santo Tomas Faculty of Medicine and Surgery, Manila, Philippines
| | - Maha Hameed
- Department of Internal Medicine, Florida State University/Sarasota Memorial Hospital, 1700 S Tamiami Trial, Sarasota, FL, 34239, USA.
| | | | - Tulika Garg
- Government Medical College and Hospital, Chandigarh, India
| | | | | | - Babu Mohan
- Department of Gastroenterology, University of Utah School of Medicine, Salt Lake City, UT, USA
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21
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Bibikova M, Fan J. Liquid biopsy for early detection of lung cancer. CHINESE MEDICAL JOURNAL PULMONARY AND CRITICAL CARE MEDICINE 2023; 1:200-206. [PMID: 39171286 PMCID: PMC11332910 DOI: 10.1016/j.pccm.2023.08.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Indexed: 08/23/2024]
Abstract
Lung cancer is the leading cause of cancer-related mortality worldwide. Early cancer detection plays an important role in improving treatment success and patient prognosis. In the past decade, liquid biopsy became an important tool for cancer diagnosis, as well as for treatment selection and response monitoring. Liquid biopsy is a broad term that defines a non-invasive test done on a sample of blood or other body fluid to look for cancer cells or other analytes that can include DNA, RNA, or other molecules released by tumor cells. Liquid biopsies mainly include circulating tumor DNA, circulating RNA, microRNA, proteins, circulating tumor cells, exosomes, and tumor-educated platelets. This review summarizes the progress and clinical application potential of liquid biopsy for early detection of lung cancer.
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Affiliation(s)
- Marina Bibikova
- AnchorDx, Inc., 46305 Landing Parkway, Fremont, CA 94538, USA
| | - Jianbing Fan
- Department of Pathology, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong 510515, China
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22
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Beylerli O, Tamrazov R, Gareev I, Ilyasova T, Shumadalova A, Bai Y, Yang B. Role of exosomal ncRNAs in traumatic brain injury. Noncoding RNA Res 2023; 8:686-692. [PMID: 37860267 PMCID: PMC10582766 DOI: 10.1016/j.ncrna.2023.10.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 09/22/2023] [Accepted: 10/07/2023] [Indexed: 10/21/2023] Open
Abstract
Traumatic brain injury (TBI) is a complex neurological disorder that often results in long-term disabilities, cognitive impairments, and emotional disturbances. Despite significant advancements in understanding the pathophysiology of TBI, effective treatments remain limited. In recent years, exosomal non-coding RNAs (ncRNAs) have emerged as potential players in TBI pathogenesis and as novel diagnostic and therapeutic targets. Exosomal ncRNAs are small RNA molecules that are secreted by cells and transported to distant sites, where they can modulate gene expression and cell signaling pathways. They have been shown to play important roles in various aspects of TBI, such as neuroinflammation, blood-brain barrier dysfunction, and neuronal apoptosis. The ability of exosomal ncRNAs to cross the blood-brain barrier and reach the brain parenchyma makes them attractive candidates for non-invasive biomarkers and drug delivery systems. However, significant challenges still need to be addressed before exosomal ncRNAs can be translated into clinical practice, including standardization of isolation and quantification methods, validation of their diagnostic and prognostic value, and optimization of their therapeutic efficacy and safety. This review aims to summarize the current knowledge regarding the role of exosomal ncRNAs in TBI, including their biogenesis, function, and potential applications in diagnosis, prognosis, and treatment. We also discuss the challenges and future perspectives of using exosomal ncRNAs as clinical tools for TBI management.
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Affiliation(s)
- Ozal Beylerli
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, People's Republic of China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, 150081, People's Republic of China
| | - Rasim Tamrazov
- Department of Oncology, Radiology and Radiotherapy, Tyumen State Medical University, 54 Odesskaya Street, 625023, Tyumen, Russia
| | - Ilgiz Gareev
- Central Research Laboratory, Bashkir State Medical University, Ufa, Republic of Bashkortostan, 3 Lenin Street, 450008, Russia
| | - Tatiana Ilyasova
- Department of Internal Diseases, Bashkir State Medical University, Ufa, Republic of Bashkortostan, 450008, Russia
| | - Alina Shumadalova
- Department of General Chemistry, Bashkir State Medical University, Ufa, Republic of Bashkortostan, 3 Lenin Street, 450008, Russia
| | - Yunlong Bai
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, People's Republic of China
| | - Baofeng Yang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, People's Republic of China
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23
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Abstract
Current lung cancer screening protocols use low-dose computed tomography scans in selected high-risk individuals. Unfortunately, utilization is low, and the rate of false-positive screens is high. Peripheral biomarkers carry meaningful promise in diagnosing and monitoring cancer with added potential advantages reducing invasive procedures and improving turnaround time. Herein, the use of such blood-based assays is considered as an adjunct to further utilization and accuracy of lung cancer screening.
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Affiliation(s)
- Nathaniel Deboever
- Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Edwin J Ostrin
- Department of General Internal Medicine, Pulmonary Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Mara B Antonoff
- Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
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24
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Martinez-Espinosa I, Serrato JA, Ortiz-Quintero B. The Role of Exosome-Derived microRNA on Lung Cancer Metastasis Progression. Biomolecules 2023; 13:1574. [PMID: 38002256 PMCID: PMC10669807 DOI: 10.3390/biom13111574] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 10/16/2023] [Accepted: 10/19/2023] [Indexed: 11/26/2023] Open
Abstract
The high mortality from lung cancer is mainly attributed to the presence of metastases at the time of diagnosis. Despite being the leading cause of lung cancer death, the underlying molecular mechanisms driving metastasis progression are still not fully understood. Recent studies suggest that tumor cell exosomes play a significant role in tumor progression through intercellular communication between tumor cells, the microenvironment, and distant organs. Furthermore, evidence shows that exosomes release biologically active components to distant sites and organs, which direct metastasis by preparing metastatic pre-niche and stimulating tumorigenesis. As a result, identifying the active components of exosome cargo has become a critical area of research in recent years. Among these components are microRNAs, which are associated with tumor progression and metastasis in lung cancer. Although research into exosome-derived microRNA (exosomal miRNAs) is still in its early stages, it holds promise as a potential target for lung cancer therapy. Understanding how exosomal microRNAs promote metastasis will provide evidence for developing new targeted treatments. This review summarizes current research on exosomal miRNAs' role in metastasis progression mechanisms, focusing on lung cancer.
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Affiliation(s)
| | | | - Blanca Ortiz-Quintero
- Department of Molecular Biomedicine and Translational Research, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City CP 14080, Mexico; (I.M.-E.); (J.A.S.)
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25
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Mullen S, Movia D. The role of extracellular vesicles in non-small-cell lung cancer, the unknowns, and how new approach methodologies can support new knowledge generation in the field. Eur J Pharm Sci 2023; 188:106516. [PMID: 37406971 DOI: 10.1016/j.ejps.2023.106516] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 06/30/2023] [Accepted: 07/01/2023] [Indexed: 07/07/2023]
Abstract
Extracellular vesicles (EVs) are nanosized particles released from most human cell types that contain a variety of cargos responsible for mediating cell-to-cell and organ-to-organ communications. Current knowledge demonstrates that EVs also play critical roles in many aspects of the progression of Non-Small-Cell Lung Cancer (NSCLC). Their roles range from increasing proliferative signalling to inhibiting apoptosis, promoting cancer metastasis, and modulating the tumour microenvironment to support cancer development. However, due to the limited availability of patient samples, intrinsic inter-species differences between human and animal EV biology, and the complex nature of EV interactions in vivo, where multiple cell types are present and several events occur simultaneously, the use of conventional preclinical and clinical models has significantly hindered reaching conclusive results. This review discusses the biological roles that EVs are currently known to play in NSCLC and identifies specific challenges in advancing today's knowledge. It also describes the NSCLC models that have been used to define currently-known EV functions, the limitations associated with their use in this field, and how New Approach Methodologies (NAMs), such as microfluidic platforms, organoids, and spheroids, can be used to overcome these limitations, effectively supporting future exciting discoveries in the NSCLC field and the potential clinical exploitation of EVs.
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Affiliation(s)
- Sive Mullen
- Applied Radiation Therapy Trinity (ARTT), Discipline of Radiation Therapy, School of Medicine, Trinity College Dublin, Trinity Centre for Health Sciences, James's Street, Dublin, Ireland; Laboratory for Biological Characterisation of Advanced Materials (LBCAM), Trinity Translational Medicine Institute (TTMI), Trinity College Dublin, Trinity Centre for Health Sciences, James's Street, Dublin, Ireland
| | - Dania Movia
- Applied Radiation Therapy Trinity (ARTT), Discipline of Radiation Therapy, School of Medicine, Trinity College Dublin, Trinity Centre for Health Sciences, James's Street, Dublin, Ireland; Laboratory for Biological Characterisation of Advanced Materials (LBCAM), Trinity Translational Medicine Institute (TTMI), Trinity College Dublin, Trinity Centre for Health Sciences, James's Street, Dublin, Ireland; Trinity St James's Cancer Institute, James's Street, Dublin, Ireland.
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26
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Khan NA, Asim M, Biswas KH, Alansari AN, Saman H, Sarwar MZ, Osmonaliev K, Uddin S. Exosome nanovesicles as potential biomarkers and immune checkpoint signaling modulators in lung cancer microenvironment: recent advances and emerging concepts. J Exp Clin Cancer Res 2023; 42:221. [PMID: 37641132 PMCID: PMC10463467 DOI: 10.1186/s13046-023-02753-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 07/08/2023] [Indexed: 08/31/2023] Open
Abstract
Lung cancer remains the leading cause of cancer-related deaths globally, and the survival rate remains low despite advances in diagnosis and treatment. The progression of lung cancer is a multifaceted and dynamic phenomenon that encompasses interplays among cancerous cells and their microenvironment, which incorporates immune cells. Exosomes, which are small membrane-bound vesicles, are released by numerous cell types in normal and stressful situations to allow communication between cells. Tumor-derived exosomes (TEXs) possess diverse neo-antigens and cargoes such as proteins, RNA, and DNA and have a unique molecular makeup reflecting tumor genetic complexity. TEXs contain both immunosuppressive and immunostimulatory factors and may play a role in immunomodulation by influencing innate and adaptive immune components. Moreover, they transmit signals that contribute to the progression of lung cancer by promoting metastasis, epithelial-mesenchymal transition (EMT), angiogenesis, and immunosuppression. This makes them a valuable resource for investigating the immune environment of tumors, which could pave the way for the development of non-invasive biomarkers that could aid in the prognosis, diagnosis, and immunotherapy of lung cancer. While immune checkpoint inhibitor (ICI) immunotherapy has shown promising results in treating initial-stage cancers, most patients eventually develop adaptive resistance over time. Emerging evidence demonstrates that TEXs could serve as a prognostic biomarker for immunotherapeutic response and have a significant impact on both systemic immune suppression and tumor advancement. Therefore, understanding TEXs and their role in lung cancer tumorigenesis and their response to immunotherapies is an exciting research area and needs further investigation. This review highlights the role of TEXs as key contributors to the advancement of lung cancer and their clinical significance in lung immune-oncology, including their possible use as biomarkers for monitoring disease progression and prognosis, as well as emerging shreds of evidence regarding the possibility of using exosomes as targets to improve lung cancer therapy.
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Affiliation(s)
- Naushad Ahmad Khan
- Department of Surgery, Trauma and Vascular Surgery Clinical Research, Hamad General Hospital, 3050, Doha, Qatar.
- Faculty of Medical Sciences, Ala-Too International University, Bishkek, Kyrgyzstan.
| | - Mohammad Asim
- Department of Surgery, Trauma and Vascular Surgery Clinical Research, Hamad General Hospital, 3050, Doha, Qatar
| | - Kabir H Biswas
- Division of Biological and Biomedical Sciences, College of Health & Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Amani N Alansari
- Department of Surgery, Trauma and Vascular Surgery Clinical Research, Hamad General Hospital, 3050, Doha, Qatar
| | - Harman Saman
- Department of Medicine, Hazm Maubrairek Hospital, Al-Rayyan, Doha, 3050, Qatar
| | | | | | - Shahab Uddin
- Translational Research Institute & Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, 3050, Qatar.
- Department of Biosciences, Integral University, Lucknow, 226026, UP, India.
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27
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Sonbhadra S, Mehak, Pandey LM. Biogenesis, Isolation, and Detection of Exosomes and Their Potential in Therapeutics and Diagnostics. BIOSENSORS 2023; 13:802. [PMID: 37622888 PMCID: PMC10452587 DOI: 10.3390/bios13080802] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/01/2023] [Accepted: 08/05/2023] [Indexed: 08/26/2023]
Abstract
The increasing research and rapid developments in the field of exosomes provide insights into their role and significance in human health. Exosomes derived from various sources, such as mesenchymal stem cells, cardiac cells, and tumor cells, to name a few, can be potential therapeutic agents for the treatment of diseases and could also serve as biomarkers for the early detection of diseases. Cellular components of exosomes, several proteins, lipids, and miRNAs hold promise as novel biomarkers for the detection of various diseases. The structure of exosomes enables them as drug delivery vehicles. Since exosomes exhibit potential therapeutic applications, their efficient isolation from complex biological/clinical samples and precise real-time analysis becomes significant. With the advent of microfluidics, nano-biosensors are being designed to capture exosomes efficiently and rapidly. Herein, we have summarized the history, biogenesis, characteristics, functions, and applications of exosomes, along with the isolation, detection, and quantification techniques. The implications of surface modifications to enhance specificity have been outlined. The review also sheds light on the engineered nanoplatforms being developed for exosome detection and capture.
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Affiliation(s)
| | | | - Lalit M. Pandey
- Bio-Interface & Environmental Engineering Lab, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India; (S.S.); (M.)
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28
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Afridi W, Strachan S, Kasetsirikul S, Pannu AS, Soda N, Gough D, Nguyen NT, Shiddiky MJA. Potential Avenues for Exosomal Isolation and Detection Methods to Enhance Small-Cell Lung Cancer Analysis. ACS MEASUREMENT SCIENCE AU 2023; 3:143-161. [PMID: 37360040 PMCID: PMC10288614 DOI: 10.1021/acsmeasuresciau.2c00068] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/02/2023] [Accepted: 02/03/2023] [Indexed: 06/28/2023]
Abstract
Around the world, lung cancer has long been the main factor in cancer-related deaths, with small-cell lung cancer (SCLC) being the deadliest form of lung cancer. Cancer cell-derived exosomes and exosomal miRNAs are considered promising biomarkers for diagnosing and prognosis of various diseases, including SCLC. Due to the rapidity of SCLC metastasis, early detection and diagnosis can offer better diagnosis and prognosis and therefore increase the patient's chances of survival. Over the past several years, many methodologies have been developed for analyzing non-SCLC-derived exosomes. However, minimal advances have been made in SCLC-derived exosome analysis methodologies. This Review discusses the epidemiology and prominent biomarkers of SCLC. Followed by a discussion about the effective strategies for isolating and detecting SCLC-derived exosomes and exosomal miRNA, highlighting the critical challenges and limitations of current methodologies. Finally, an overview is provided detailing future perspectives for exosome-based SCLC research.
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Affiliation(s)
- Waqar
Ahmed Afridi
- School
of Environment and Science, Griffith University, Nathan Campus, Nathan, QLD 4111, Australia
- Queensland
Micro and Nanotechnology Centre, Griffith
University, Nathan Campus, Nathan, QLD 4111, Australia
| | - Simon Strachan
- School
of Environment and Science, Griffith University, Nathan Campus, Nathan, QLD 4111, Australia
- Queensland
Micro and Nanotechnology Centre, Griffith
University, Nathan Campus, Nathan, QLD 4111, Australia
| | - Surasak Kasetsirikul
- Queensland
Micro and Nanotechnology Centre, Griffith
University, Nathan Campus, Nathan, QLD 4111, Australia
| | - Amandeep Singh Pannu
- Queensland
Micro and Nanotechnology Centre, Griffith
University, Nathan Campus, Nathan, QLD 4111, Australia
| | - Narshone Soda
- Queensland
Micro and Nanotechnology Centre, Griffith
University, Nathan Campus, Nathan, QLD 4111, Australia
| | - Daniel Gough
- Centre
for Cancer Research, Hudson Institute of
Medical Research, Clayton, Vic 3168, Australia
- Department
of Molecular and Translational Science, Monash University, Clayton, Vic 3168, Australia
| | - Nam-Trung Nguyen
- Queensland
Micro and Nanotechnology Centre, Griffith
University, Nathan Campus, Nathan, QLD 4111, Australia
| | - Muhammad J. A. Shiddiky
- School
of Environment and Science, Griffith University, Nathan Campus, Nathan, QLD 4111, Australia
- Queensland
Micro and Nanotechnology Centre, Griffith
University, Nathan Campus, Nathan, QLD 4111, Australia
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29
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Li YZ, Kong SN, Liu YP, Yang Y, Zhang HM. Can Liquid Biopsy Based on ctDNA/cfDNA Replace Tissue Biopsy for the Precision Treatment of EGFR-Mutated NSCLC? J Clin Med 2023; 12:jcm12041438. [PMID: 36835972 PMCID: PMC9966257 DOI: 10.3390/jcm12041438] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 01/16/2023] [Accepted: 02/06/2023] [Indexed: 02/15/2023] Open
Abstract
More and more clinical trials have explored the role of liquid biopsy in the diagnosis and treatment of EGFR-mutated NSCLC. In certain circumstances, liquid biopsy has unique advantages and offers a new way to detect therapeutic targets, analyze drug resistance mechanisms in advanced patients, and monitor MRD in patients with operable NSCLC. Although its potential cannot be ignored, more evidence is needed to support the transition from the research stage to clinical application. We reviewed the latest progress in research on the efficacy and resistance mechanisms of targeted therapy for advanced NSCLC patients with plasma ctDNA EGFR mutation and the evaluation of MRD based on ctDNA detection in perioperative and follow-up monitoring.
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30
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Lin X, Cai Y, Zong C, Chen B, Shao D, Cui H, Li Z, Xu P. Bronchoalveolar Lavage as Potential Diagnostic Specimens to Genetic Testing in Advanced Nonsmall Cell Lung Cancer. Technol Cancer Res Treat 2023; 22:15330338231202881. [PMID: 37743841 PMCID: PMC10521282 DOI: 10.1177/15330338231202881] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 07/24/2023] [Accepted: 08/22/2023] [Indexed: 09/26/2023] Open
Abstract
Background: There is limited knowledge on the yield of performing capture-based targeted ultradeep sequencing on bronchoalveolar lavage (BAL) specimens from advanced nonsmall cell lung cancer (NSCLC) patients. This study aimed to evaluate gene variations and performance characteristics in BAL and tissue specimens using targeted sequencing. Methods: This cohort study retrospectively enrolled 20 patients with advanced NSCLC. The variant detection percentage, correlation of tumor mutation burden (TMB), and allele frequency heterogeneity (AFH) were compared between paired BAL and tissue samples. A three-tiered system was also applied for the interpretation of gene variants according to the guidelines. Results: No statistical difference was observed in variant detection between BAL and tissue samples (P = .591 for variant tier and P = .409 for variant type). In general, BAL achieved higher detection rates in tier I variants (96.2% vs 84.6%) and gene fusions (75% vs 50%) compared with tissue samples; tissue samples had better variants detection rates for other variants, such as tier II (89.6% vs 76.0%), tier III (87.1% vs 72.6%), single nucleotide variant (SNV, 89.6% vs 76.5%), insertion/deletion/duplication (InDel, 74.6% vs 69.8%) and copy number variation (CNV, 93.8% vs 43.8%). Besides, there were significant correlations of TMB (R2 = 0.96, P < .001) and AFH (R2 = 0.87, P < .001) between BALs and paired tissues. Conclusions: The findings demonstrate that BAL may serve as a supplement in liquid biopsy for mutation detection and for routine utilization in clinical settings.
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Affiliation(s)
- Xuwen Lin
- Respiratory Department, Peking University Shenzhen Hospital, Shenzhen, China
| | - Yazhou Cai
- Respiratory Department, Peking University Shenzhen Hospital, Shenzhen, China
| | - Chenyu Zong
- Respiratory Department, Peking University Shenzhen Hospital, Shenzhen, China
| | | | - Di Shao
- BGI Genomics, BGI-Shenzhen, Shenzhen, China
| | - Hao Cui
- Zhuhai Maternal and Child Health Hospital, Zhuhai, China
| | - Zheng Li
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Ping Xu
- Respiratory Department, Peking University Shenzhen Hospital, Shenzhen, China
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31
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Prolonged Exposure to Simulated Microgravity Changes Release of Small Extracellular Vesicle in Breast Cancer Cells. Int J Mol Sci 2022; 23:ijms232416095. [PMID: 36555738 PMCID: PMC9781806 DOI: 10.3390/ijms232416095] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/14/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Breast cancer is the leading cause of cancer incidence worldwide and among the five leading causes of cancer mortality. Despite major improvements in early detection and new treatment approaches, the need for better outcomes and quality of life for patients is still high. Extracellular vesicles play an important role in tumor biology, as they are able to transfer information between cells of different origins and locations. Their potential value as biomarkers or for targeted tumor therapy is apparent. In this study, we analyzed the supernatants of MCF-7 breast cancer cells, which were harvested following 5 or 10 days of simulated microgravity on a Random Positioning Machine (RPM). The primary results showed a substantial increase in released vesicles following incubation under simulated microgravity at both time points. The distribution of subpopulations regarding their surface protein expression is also altered; the minimal changes between the time points hint at an early adaption. This is the first step in gaining further insight into the mechanisms of tumor progression, metastasis, the education of the tumor microenvironments, and preparation of the metastatic niche. Additionally, this may lighten up the processes of the rapid cellular adaptions in the organisms of space travelers during spaceflights.
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32
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Zippoli M, Ruocco A, Novelli R, Rocchio F, Miscione MS, Allegretti M, Cesta MC, Amendola PG. The role of extracellular vesicles and interleukin-8 in regulating and mediating neutrophil-dependent cancer drug resistance. Front Oncol 2022; 12:947183. [PMID: 36591453 PMCID: PMC9800989 DOI: 10.3389/fonc.2022.947183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 10/24/2022] [Indexed: 12/23/2022] Open
Abstract
Tumor drug resistance is a multifactorial and heterogenous condition that poses a serious burden in clinical oncology. Given the increasing incidence of resistant tumors, further understanding of the mechanisms that make tumor cells able to escape anticancer drug effects is pivotal for developing new effective treatments. Neutrophils constitute a considerable proportion of tumor infiltrated immune cells, and studies have linked elevated neutrophil counts with poor prognosis. Tumor-associated neutrophils (TANs) can acquire in fact immunoregulatory capabilities, thus regulating tumor progression and resistance, or response to therapy. In this review, we will describe TANs' actions in the tumor microenvironment, with emphasis on the analysis of the role of interleukin-8 (IL-8) and extracellular vesicles (EVs) as crucial modulators and mediators of TANs biology and function in tumors. We will then discuss the main mechanisms through which TANs can induce drug resistance, finally reporting emerging therapeutic approaches that target these mechanisms and can thus be potentially used to reduce or overcome neutrophil-mediated tumor drug resistance.
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Affiliation(s)
- Mara Zippoli
- Research and Development (R&D), Dompé farmaceutici S.p.A., Naples, Italy
| | - Anna Ruocco
- Research and Development (R&D), Dompé farmaceutici S.p.A., Naples, Italy
| | - Rubina Novelli
- Research and Development (R&D), Dompé farmaceutici S.p.A., Milan, Italy
| | - Francesca Rocchio
- Research and Development (R&D), Dompé farmaceutici S.p.A., Naples, Italy
| | - Martina Sara Miscione
- Research and Development (R&D), Dompé farmaceutici S.p.A., Naples, Italy,Department of Biotechnological and Applied Clinical Science, University of L'Aquila, L'Aquila, Italy
| | | | | | - Pier Giorgio Amendola
- Research and Development (R&D), Dompé farmaceutici S.p.A., Naples, Italy,*Correspondence: Pier Giorgio Amendola,
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33
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Temperini ME, Di Giacinto F, Romanò S, Di Santo R, Augello A, Polito R, Baldassarre L, Giliberti V, Papi M, Basile U, Niccolini B, Krasnowska EK, Serafino A, De Spirito M, Di Gaspare A, Ortolani M, Ciasca G. Antenna-enhanced mid-infrared detection of extracellular vesicles derived from human cancer cell cultures. J Nanobiotechnology 2022; 20:530. [PMID: 36514065 PMCID: PMC9746222 DOI: 10.1186/s12951-022-01693-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 10/30/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Extracellular Vesicles (EVs) are sub-micrometer lipid-bound particles released by most cell types. They are considered a promising source of cancer biomarkers for liquid biopsy and personalized medicine due to their specific molecular cargo, which provides biochemical information on the state of parent cells. Despite this potential, EVs translation process in the diagnostic practice is still at its birth, and the development of novel medical devices for their detection and characterization is highly required. RESULTS In this study, we demonstrate mid-infrared plasmonic nanoantenna arrays designed to detect, in the liquid and dry phase, the specific vibrational absorption signal of EVs simultaneously with the unspecific refractive index sensing signal. For this purpose, EVs are immobilized on the gold nanoantenna surface by immunocapture, allowing us to select specific EV sub-populations and get rid of contaminants. A wet sample-handling technique relying on hydrophobicity contrast enables effortless reflectance measurements with a Fourier-transform infrared (FTIR) spectro-microscope in the wavelength range between 10 and 3 µm. In a proof-of-principle experiment carried out on EVs released from human colorectal adenocarcinoma (CRC) cells, the protein absorption bands (amide-I and amide-II between 5.9 and 6.4 µm) increase sharply within minutes when the EV solution is introduced in the fluidic chamber, indicating sensitivity to the EV proteins. A refractive index sensing curve is simultaneously provided by our sensor in the form of the redshift of a sharp spectral edge at wavelengths around 5 µm, where no vibrational absorption of organic molecules takes place: this permits to extract of the dynamics of EV capture by antibodies from the overall molecular layer deposition dynamics, which is typically measured by commercial surface plasmon resonance sensors. Additionally, the described metasurface is exploited to compare the spectral response of EVs derived from cancer cells with increasing invasiveness and metastatic potential, suggesting that the average secondary structure content in EVs can be correlated with cell malignancy. CONCLUSIONS Thanks to the high protein sensitivity and the possibility to work with small sample volumes-two key features for ultrasensitive detection of extracellular vesicles- our lab-on-chip can positively impact the development of novel laboratory medicine methods for the molecular characterization of EVs.
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Affiliation(s)
- Maria Eleonora Temperini
- Department of Physics, Sapienza University of Rome, Piazzale Aldo Moro 2, 00185, Rome, Italy
- Center for Life Neuro and Nano Sciences IIT@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161, Rome, Italy
| | - Flavio Di Giacinto
- Fondazione Policlinico Universitario "A. Gemelli", IRCCS, Rome, Italy
- Dipartimento di Neuroscienze, Sezione di Fisica, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Sabrina Romanò
- Fondazione Policlinico Universitario "A. Gemelli", IRCCS, Rome, Italy
- Dipartimento di Neuroscienze, Sezione di Fisica, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Riccardo Di Santo
- Fondazione Policlinico Universitario "A. Gemelli", IRCCS, Rome, Italy
| | - Alberto Augello
- Fondazione Policlinico Universitario "A. Gemelli", IRCCS, Rome, Italy
| | - Raffaella Polito
- Department of Physics, Sapienza University of Rome, Piazzale Aldo Moro 2, 00185, Rome, Italy
| | - Leonetta Baldassarre
- Department of Physics, Sapienza University of Rome, Piazzale Aldo Moro 2, 00185, Rome, Italy
| | - Valeria Giliberti
- Center for Life Neuro and Nano Sciences IIT@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161, Rome, Italy
| | - Massimiliano Papi
- Fondazione Policlinico Universitario "A. Gemelli", IRCCS, Rome, Italy
- Dipartimento di Neuroscienze, Sezione di Fisica, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Umberto Basile
- Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, 00168, Rome, Italy
| | - Benedetta Niccolini
- Dipartimento di Neuroscienze, Sezione di Fisica, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Ewa K Krasnowska
- Institute of Translational Pharmacology, National Research Council of Italy, Rome, Italy
| | - Annalucia Serafino
- Institute of Translational Pharmacology, National Research Council of Italy, Rome, Italy
| | - Marco De Spirito
- Fondazione Policlinico Universitario "A. Gemelli", IRCCS, Rome, Italy
- Dipartimento di Neuroscienze, Sezione di Fisica, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Alessandra Di Gaspare
- Fondazione Policlinico Universitario "A. Gemelli", IRCCS, Rome, Italy
- NEST, CNR-Istituto Nanoscienze and Scuola Normale Superiore, Piazza San Silvestro 12, 56127, Pisa, Italy
| | - Michele Ortolani
- Department of Physics, Sapienza University of Rome, Piazzale Aldo Moro 2, 00185, Rome, Italy.
- Center for Life Neuro and Nano Sciences IIT@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161, Rome, Italy.
| | - Gabriele Ciasca
- Fondazione Policlinico Universitario "A. Gemelli", IRCCS, Rome, Italy.
- Dipartimento di Neuroscienze, Sezione di Fisica, Università Cattolica del Sacro Cuore, Rome, Italy.
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Cancer-derived exosomal miR-197-3p confers angiogenesis via targeting TIMP2/3 in lung adenocarcinoma metastasis. Cell Death Dis 2022; 13:1032. [PMID: 36494333 PMCID: PMC9734149 DOI: 10.1038/s41419-022-05420-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 11/01/2022] [Accepted: 11/08/2022] [Indexed: 12/13/2022]
Abstract
Cancer-derived exosomal miRNAs are implicated in tumorigenesis and development of lung adenocarcinoma (LUAD). The objective of this study is to unravel the biological function of exosomal miR-197-3p in LUAD metastasis. qRT-PCR showed that elevated miR-197-3p in LUAD tissues was positively correlated with LUAD metastasis. CCK-8, tube formation, transwell and wound healing assays revealed that exosomal miR-197-3p from LUAD cells promoted the proliferation, angiogenesis and migration of HUVECs in vitro. LUAD cells-derived exosomal miR-197-3p also facilitated tumor growth and angiogenesis in LUAD cells-derived tumor xenograft model. TIMP2 and TIMP3 were identified as target genes of miR-197-3p in HUVECs by bioinformatics analysis and luciferase reporter assay. Functional studies illustrated that exosomal miR-197-3p promoted angiogenesis and migration via targeting TIMP2 and TIMP3 in HUVECs. In vivo data further supported that exosomal miR-197-3p promoted lung metastasis via TIMP2/3-mediated angiogenesis. In conclusion, LUAD cells-derived exosomal miR-197-3p conferred angiogenesis via targeting TIMP2/3 in LUAD metastasis.
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Alexeyenko A, Brustugun OT, Eide IJZ, Gencheva R, Kosibaty Z, Lai Y, de Petris L, Tsakonas G, Grundberg O, Franzen B, Viktorsson K, Lewensohn R, Hydbring P, Ekman S. Plasma RNA profiling unveils transcriptional signatures associated with resistance to osimertinib in EGFR T790M positive non-small cell lung cancer patients. Transl Lung Cancer Res 2022; 11:2064-2078. [PMID: 36386450 PMCID: PMC9641044 DOI: 10.21037/tlcr-22-236] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 08/22/2022] [Indexed: 09/10/2023]
Abstract
BACKGROUND Targeted therapy with tyrosine kinases inhibitors (TKIs) against epidermal growth factor receptor (EGFR) is part of routine clinical practice for EGFR mutant advanced non-small cell lung cancer (NSCLC) patients. These patients eventually develop resistance, frequently accompanied by a gatekeeper mutation, T790M. Osimertinib is a third-generation EGFR TKI displaying potency to the T790M resistance mutation. Here we aimed to analyze if exosomal RNAs, isolated from longitudinally sampled plasma of osimertinib-treated EGFR T790M NSCLC patients, could provide biomarkers of acquired resistance to osimertinib. METHODS Plasma was collected at baseline and progression of disease from 20 patients treated with osimertinib in the multicenter phase II study TKI in Relapsed EGFR-mutated non-small cell lung cancer patients (TREM). Plasma was centrifuged at 16,000 g followed by exosomal RNA extraction using Qiagen exoRNeasy kit. RNA was subjected to transcriptomics analysis with Clariom D. RESULTS Transcriptome profiling revealed differential expression [log2(fold-change) >0.25, false discovery rate (FDR) P<0.15, and P(interaction) >0.05] of 128 transcripts. We applied network enrichment analysis (NEA) at the pathway level in a large collection of functional gene sets. This overall enrichment analysis revealed alterations in pathways related to EGFR and PI3K as well as to syndecan and glypican pathways (NEA FDR <3×10-10). When applied to the 40 individual, sample-specific gene sets, the NEA detected 16 immune-related gene sets (FDR <0.25, P(interaction) >0.05 and NEA z-score exceeding 3 in at least one sample). CONCLUSIONS Our study demonstrates a potential usability of plasma-derived exosomal RNAs to characterize molecular phenotypes of emerging osimertinib resistance. Furthermore, it highlights the involvement of multiple RNA species in shaping the transcriptome landscape of osimertinib-refractory NSCLC patients.
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Affiliation(s)
- Andrey Alexeyenko
- Science for Life Laboratory, Box 1031, Solna, Sweden
- Evi-networks consulting, Huddinge, Sweden
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden
| | - Odd Terje Brustugun
- Section of Oncology, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Cancer Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Inger Johanne Zwicky Eide
- Section of Oncology, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Cancer Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Radosveta Gencheva
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Zeinab Kosibaty
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Yi Lai
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Luigi de Petris
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
- Thoracic Oncology Center, Karolinska University Hospital, Stockholm, Sweden
| | - Georgios Tsakonas
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
- Thoracic Oncology Center, Karolinska University Hospital, Stockholm, Sweden
| | - Oscar Grundberg
- Thoracic Oncology Center, Karolinska University Hospital, Stockholm, Sweden
| | - Bo Franzen
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Kristina Viktorsson
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Rolf Lewensohn
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
- Thoracic Oncology Center, Karolinska University Hospital, Stockholm, Sweden
| | - Per Hydbring
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Simon Ekman
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
- Thoracic Oncology Center, Karolinska University Hospital, Stockholm, Sweden
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Recent advances in integrated microfluidics for liquid biopsies and future directions. Biosens Bioelectron 2022; 217:114715. [PMID: 36174359 DOI: 10.1016/j.bios.2022.114715] [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: 10/26/2021] [Revised: 07/20/2022] [Accepted: 09/09/2022] [Indexed: 12/12/2022]
Abstract
Liquid biopsies have piqued the interest of researchers as a new tumor diagnosis technique due to their unique benefits of non-invasiveness, sensitivity, and convenience. Recent advances in microfluidic technology have integrated separation, purification, and detection, allowing for high-throughput, high-sensitivity, and high-controllability detection of specific biomarkers in liquid biopsies. With the increasing demand for tumor detection and individualized treatment, new challenges are emerging for the ever-improving microfluidic technology. The state-of-the-art microfluidic design and fabrications have been reviewed in this manuscript, and how this technology can be applied to liquid biopsies from the point of view of the detection process. The primary discussion objectives are circulating tumor cells (CTCs), exosomes, and circulating nucleic acid (ctDNA). Furthermore, the challenges and future direction of microfluidic technology in detecting liquid biomarkers have been discussed.
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Jangholi A, Müller Bark J, Kenny L, Vasani S, Rao S, Dolcetti R, Punyadeera C. Exosomes at the crossroad between therapeutic targets and therapy resistance in head and neck squamous cell carcinoma. Biochim Biophys Acta Rev Cancer 2022; 1877:188784. [PMID: 36028150 DOI: 10.1016/j.bbcan.2022.188784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/18/2022] [Accepted: 08/19/2022] [Indexed: 11/24/2022]
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are aggressive and clinically challenging tumours that require a multidisciplinary management approach. Despite significant therapy improvements, HNSCC patients have a poor prognosis with a 5-year survival rate of about 65%. As recently recognised key players in cancer, exosomes are extracellular vesicles (EVs) with a diameter of nearly 50-120 nm which transport information from one cell to another. Exosomes are actively involved in various aspects of tumour initiation, development, metastasis, immune regulation, therapy resistance, and therapeutic applications. However, current knowledge of the role of exosomes in the pathophysiological processes of HNSCC is still in its infancy, and additional studies are needed. In this review, we summarise and discuss the relevance of exosomes in mediating local immunosuppression and therapy resistance of HNSCC. We also review the most recent studies that have explored the therapeutic potential of exosomes as cancer vaccines, drug carriers or tools to reverse the drug resistance of HNSCC.
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Affiliation(s)
- Abolfazl Jangholi
- Centre for Biomedical Technologies, The School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, QLD, Australia; The School of Environment and Science, Griffith Institute for Drug Discovery (GRIDD), Griffith University, Brisbane, Australia
| | - Juliana Müller Bark
- The School of Environment and Science, Griffith Institute for Drug Discovery (GRIDD), Griffith University, Brisbane, Australia
| | - Lizbeth Kenny
- Royal Brisbane and Women's Hospital, Cancer Care Services, Herston, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Sarju Vasani
- Royal Brisbane and Women's Hospital, Cancer Care Services, Herston, Australia; Department of Otolaryngology, Royal Brisbane and Women's Hospital, Herston, Australia
| | - Sudha Rao
- Gene Regulation and Translational Medicine Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Riccardo Dolcetti
- Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria 3010, Australia; Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia; The University of Queensland Diamantina Institute, Brisbane, QLD, Australia
| | - Chamindie Punyadeera
- The School of Environment and Science, Griffith Institute for Drug Discovery (GRIDD), Griffith University, Brisbane, Australia; Menzies Health Institute Queensland (MIHQ), Griffith University, Gold Coast, Australia.
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Majood M, Rawat S, Mohanty S. Delineating the role of extracellular vesicles in cancer metastasis: A comprehensive review. Front Immunol 2022; 13:966661. [PMID: 36059497 PMCID: PMC9439583 DOI: 10.3389/fimmu.2022.966661] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 08/01/2022] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) are subcellular messengers that aid in the formation and spread of cancer by enabling tumor-stroma communication. EVs develop from the very porous structure of late endosomes and hold information on both the intrinsic “status” of the cell and the extracellular signals absorbed by the cells from their surroundings. These EVs contain physiologically useful components, including as nucleic acids, lipids, and proteins, which have been found to activate important signaling pathways in tumor and tumor microenvironment (TME) cells, aggravating tumor growth. We highlight critical cell biology mechanisms that link EVS formation to cargo sorting in cancer cells in this review.Sorting out the signals that control EVs creation, cargo, and delivery will aid our understanding of carcinogenesis. Furthermore, we reviewed how cancer development and spreading behaviors are affected by coordinated communication between malignant and non-malignant cells. Herein, we studied the reciprocal exchanges via EVs in various cancer types. Further research into the pathophysiological functions of various EVs in tumor growth is likely to lead to the discovery of new biomarkers in liquid biopsy and the development of tumor-specific therapies.
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Precise assessment of lung cancer-derived exosomes based on dual-labelled membrane interface. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2022.07.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Shi L, Zhu W, Huang Y, Zhuo L, Wang S, Chen S, Zhang B, Ke B. Cancer-associated fibroblast-derived exosomal microRNA-20a suppresses the PTEN/PI3K-AKT pathway to promote the progression and chemoresistance of non-small cell lung cancer. Clin Transl Med 2022; 12:e989. [PMID: 35857905 PMCID: PMC9299573 DOI: 10.1002/ctm2.989] [Citation(s) in RCA: 99] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 07/02/2022] [Accepted: 07/07/2022] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Cancer-associated fibroblasts (CAFs) contributes to overall tumor progression. In the current survey, we explored the ability of microRNA-20a (miR-20a) within these CAF-derived exosomes to influence non-small-cell lung cancer (NSCLC) progression. MATERIALS AND METHODS Normal tissue-associated fibroblasts (NAFs) and CAFs were collected from samples of NSCLC patient tumors and paracancerous lung tissues. Exosomes derived from these cells were then characterized via Western blotting, nanoparticle tracking analyses, and transmission electron microscopy. The expression of miR-20a was assessed via qPCR and fluorescence in situ hybridization (FISH). CCK-8, EdU uptake, and colony formation assessments were used for evaluating tumor proliferation, while Hoechst staining was performed to monitor the in vitro apoptotic death of tumor cells. A model of xenograft tumor established in nude mice was also used to evaluate in vivo tumor responses. RESULTS CAF-derived exosomes exhibited miR-20a upregulation and promoted NSCLC cell proliferation and resistance to cisplatin (DDP). Mechanistically, CAF-derived exosomes were discovered to transmit miR-20a to tumor cells wherein it was able to target PTEN to enhance DDP resistance and proliferation. Associated PTEN downregulation following exosome-derived miR-20a treatment enhanced PI3K/AKT pathway activation. CONCLUSION The achieved outcomes explain that CAFs can release miR-20a-containing exosomes capable of promoting NSCLC progression and chemoresistance, highlighting this pathway as a possible therapeutic target in NSCLC.
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Affiliation(s)
- Lin Shi
- Department of Traditional Chinese MedicineZhujiang Hospital of Southern Medical UniversityGuangzhouChina
| | - Weiliang Zhu
- Department of Cancer CenterZhujiang Hospital of Southern Medical UniversityGuangzhouChina
| | - Yuanyuan Huang
- Department of VIP RegionState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center of Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Lin Zhuo
- Department of Traditional Chinese MedicineZhujiang Hospital of Southern Medical UniversityGuangzhouChina
| | - Siyun Wang
- Department of Traditional Chinese MedicineZhujiang Hospital of Southern Medical UniversityGuangzhouChina
| | - Shaobing Chen
- Department of Traditional Chinese MedicineZhujiang Hospital of Southern Medical UniversityGuangzhouChina
| | - Bei Zhang
- Department of VIP RegionState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center of Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Bin Ke
- Department of VIP RegionState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center of Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
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Duréndez-Sáez E, Calabuig-Fariñas S, Torres-Martínez S, Moreno-Manuel A, Herreros-Pomares A, Escorihuela E, Mosqueda M, Gallach S, Guijarro R, Serna E, Suárez-Cabrera C, Paramio JM, Blasco A, Camps C, Jantus-Lewintre E. Analysis of Exosomal Cargo Provides Accurate Clinical, Histologic and Mutational Information in Non-Small Cell Lung Cancer. Cancers (Basel) 2022; 14:cancers14133216. [PMID: 35804987 PMCID: PMC9264915 DOI: 10.3390/cancers14133216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/24/2022] [Accepted: 06/27/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary Non-small cell lung cancer (NSCLC) is the second most commonly diagnosed cancer and the leading cause of cancer-related death worldwide. Clinical decision-making depends on the histological classification; however, tissue biopsy is frequently not technically feasible due to tumor location or limited tissue samples. Therefore, we propose to find clinical, molecular and histological biomarkers using a minimally invasive approach based on the analysis of the cargo of the blood extracellular vesicles. Exosomes are membranous vesicles present in several biological fluids, which carry biological information to distant tissues, regulating several tumor processes. This study aims to analyze NSCLC exosome cargo for search biomarkers that could improve clinical management. This report demonstrates the possibility of implementing exosomes to detect molecular alterations and as a source of biomarkers to differentiate NSCLC histology, allowing for a new approach in precision oncology. Abstract Lung cancer is a malignant disease with high mortality and poor prognosis, frequently diagnosed at advanced stages. Nowadays, immense progress in treatment has been achieved. However, the present scenario continues to be critical, and a full comprehension of tumor progression mechanisms is required, with exosomes being potentially relevant players. Exosomes are membranous vesicles that contain biological information, which can be transported cell-to-cell and modulate relevant processes in the hallmarks of cancer. The present research aims to characterize the exosomes’ cargo and study their role in NSCLC to identify biomarkers. We analyzed exosomes secreted by primary cultures and cell lines, grown in monolayer and tumorsphere formations. Exosomal DNA content showed molecular alterations, whereas RNA high-throughput analysis resulted in a pattern of differentially expressed genes depending on histology. The most significant differences were found in XAGE1B, CABYR, NKX2-1, SEPP1, CAPRIN1, and RIOK3 genes when samples from two independent cohorts of resected NSCLC patients were analyzed. We identified and validated biomarkers for adenocarcinoma and squamous cell carcinoma. Our results could represent a relevant contribution concerning exosomes in clinical practice, allowing for the identification of biomarkers that provide information regarding tumor features, prognosis and clinical behavior of the disease.
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Affiliation(s)
- Elena Duréndez-Sáez
- Molecular Oncology Laboratory, Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain; (E.D.-S.); (S.C.-F.); (S.T.-M.); (A.M.-M.); (A.H.-P.); (E.E.); (M.M.); (S.G.)
- TRIAL Mixed Unit, Centro Investigación Príncipe Felipe—Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain;
- Centro de Investigación Biomédica en Red Cáncer, CIBERONC, 28029 Madrid, Spain; (R.G.); (C.S.-C.); (J.M.P.)
| | - Silvia Calabuig-Fariñas
- Molecular Oncology Laboratory, Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain; (E.D.-S.); (S.C.-F.); (S.T.-M.); (A.M.-M.); (A.H.-P.); (E.E.); (M.M.); (S.G.)
- TRIAL Mixed Unit, Centro Investigación Príncipe Felipe—Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain;
- Centro de Investigación Biomédica en Red Cáncer, CIBERONC, 28029 Madrid, Spain; (R.G.); (C.S.-C.); (J.M.P.)
- Department of Pathology, Universitat de València, 46010 Valencia, Spain
| | - Susana Torres-Martínez
- Molecular Oncology Laboratory, Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain; (E.D.-S.); (S.C.-F.); (S.T.-M.); (A.M.-M.); (A.H.-P.); (E.E.); (M.M.); (S.G.)
- TRIAL Mixed Unit, Centro Investigación Príncipe Felipe—Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain;
- Centro de Investigación Biomédica en Red Cáncer, CIBERONC, 28029 Madrid, Spain; (R.G.); (C.S.-C.); (J.M.P.)
| | - Andrea Moreno-Manuel
- Molecular Oncology Laboratory, Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain; (E.D.-S.); (S.C.-F.); (S.T.-M.); (A.M.-M.); (A.H.-P.); (E.E.); (M.M.); (S.G.)
- TRIAL Mixed Unit, Centro Investigación Príncipe Felipe—Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain;
- Centro de Investigación Biomédica en Red Cáncer, CIBERONC, 28029 Madrid, Spain; (R.G.); (C.S.-C.); (J.M.P.)
| | - Alejandro Herreros-Pomares
- Molecular Oncology Laboratory, Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain; (E.D.-S.); (S.C.-F.); (S.T.-M.); (A.M.-M.); (A.H.-P.); (E.E.); (M.M.); (S.G.)
- Centro de Investigación Biomédica en Red Cáncer, CIBERONC, 28029 Madrid, Spain; (R.G.); (C.S.-C.); (J.M.P.)
- Department of Biotechnology, Universitat Politècnica de València, 46022 Valencia, Spain
| | - Eva Escorihuela
- Molecular Oncology Laboratory, Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain; (E.D.-S.); (S.C.-F.); (S.T.-M.); (A.M.-M.); (A.H.-P.); (E.E.); (M.M.); (S.G.)
- TRIAL Mixed Unit, Centro Investigación Príncipe Felipe—Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain;
- Centro de Investigación Biomédica en Red Cáncer, CIBERONC, 28029 Madrid, Spain; (R.G.); (C.S.-C.); (J.M.P.)
| | - Marais Mosqueda
- Molecular Oncology Laboratory, Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain; (E.D.-S.); (S.C.-F.); (S.T.-M.); (A.M.-M.); (A.H.-P.); (E.E.); (M.M.); (S.G.)
- TRIAL Mixed Unit, Centro Investigación Príncipe Felipe—Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain;
| | - Sandra Gallach
- Molecular Oncology Laboratory, Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain; (E.D.-S.); (S.C.-F.); (S.T.-M.); (A.M.-M.); (A.H.-P.); (E.E.); (M.M.); (S.G.)
- TRIAL Mixed Unit, Centro Investigación Príncipe Felipe—Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain;
- Centro de Investigación Biomédica en Red Cáncer, CIBERONC, 28029 Madrid, Spain; (R.G.); (C.S.-C.); (J.M.P.)
| | - Ricardo Guijarro
- Centro de Investigación Biomédica en Red Cáncer, CIBERONC, 28029 Madrid, Spain; (R.G.); (C.S.-C.); (J.M.P.)
- Department of Surgery, Universitat de València, 46010 Valencia, Spain
- Department of Thoracic Surgery, Hospital General Universitario de Valencia, 46014 Valencia, Spain
| | - Eva Serna
- Freshage Research Group, Department of Physiology, Universitat de València, 46010 Valencia, Spain;
- Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, 46010 Valencia, Spain
| | - Cristian Suárez-Cabrera
- Centro de Investigación Biomédica en Red Cáncer, CIBERONC, 28029 Madrid, Spain; (R.G.); (C.S.-C.); (J.M.P.)
- Biomedical Research Institute i+12, Hospital Universitario “12 de Octubre”, 28040 Madrid, Spain
- Molecular Oncology Unit, CIEMAT, 28045 Madrid, Spain
| | - Jesús M. Paramio
- Centro de Investigación Biomédica en Red Cáncer, CIBERONC, 28029 Madrid, Spain; (R.G.); (C.S.-C.); (J.M.P.)
- Biomedical Research Institute i+12, Hospital Universitario “12 de Octubre”, 28040 Madrid, Spain
- Molecular Oncology Unit, CIEMAT, 28045 Madrid, Spain
| | - Ana Blasco
- TRIAL Mixed Unit, Centro Investigación Príncipe Felipe—Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain;
- Centro de Investigación Biomédica en Red Cáncer, CIBERONC, 28029 Madrid, Spain; (R.G.); (C.S.-C.); (J.M.P.)
- Department of Medical Oncology, Hospital General Universitario de Valencia, 46014 Valencia, Spain
| | - Carlos Camps
- Molecular Oncology Laboratory, Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain; (E.D.-S.); (S.C.-F.); (S.T.-M.); (A.M.-M.); (A.H.-P.); (E.E.); (M.M.); (S.G.)
- TRIAL Mixed Unit, Centro Investigación Príncipe Felipe—Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain;
- Centro de Investigación Biomédica en Red Cáncer, CIBERONC, 28029 Madrid, Spain; (R.G.); (C.S.-C.); (J.M.P.)
- Department of Medical Oncology, Hospital General Universitario de Valencia, 46014 Valencia, Spain
- Department of Medicine, Universitat de València, 46010 Valencia, Spain
- Correspondence: (C.C.); (E.J.-L.)
| | - Eloisa Jantus-Lewintre
- Molecular Oncology Laboratory, Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain; (E.D.-S.); (S.C.-F.); (S.T.-M.); (A.M.-M.); (A.H.-P.); (E.E.); (M.M.); (S.G.)
- TRIAL Mixed Unit, Centro Investigación Príncipe Felipe—Fundación Investigación Hospital General Universitario de Valencia, 46014 Valencia, Spain;
- Centro de Investigación Biomédica en Red Cáncer, CIBERONC, 28029 Madrid, Spain; (R.G.); (C.S.-C.); (J.M.P.)
- Department of Biotechnology, Universitat Politècnica de València, 46022 Valencia, Spain
- Joint Unit: Nanomedicine, Centro Investigación Príncipe Felipe—Universitat Politècnica de Valencia, 46022 Valencia, Spain
- Correspondence: (C.C.); (E.J.-L.)
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Kim IA, Hur JY, Kim HJ, Kim WS, Lee KY. Extracellular Vesicle-Based Bronchoalveolar Lavage Fluid Liquid Biopsy for EGFR Mutation Testing in Advanced Non-Squamous NSCLC. Cancers (Basel) 2022; 14:cancers14112744. [PMID: 35681723 PMCID: PMC9179452 DOI: 10.3390/cancers14112744] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/25/2022] [Accepted: 05/30/2022] [Indexed: 02/05/2023] Open
Abstract
To overcome the limitations of the tissue biopsy and plasma cfDNA liquid biopsy, we performed the EV-based BALF liquid biopsy of 224 newly diagnosed stage III-IV NSCLC patients and compared it with tissue genotyping and 110 plasma liquid biopsies. Isolation of EVs from BALF was performed by ultracentrifugation. EGFR genotyping was performed through peptide nucleic acid clamping-assisted fluorescence melting curve analysis. Compared with tissue-based genotyping, BALF liquid biopsy demonstrated a sensitivity, specificity, and concordance rates of 97.8%, 96.9%, and 97.7%, respectively. The performance of BALF liquid biopsy was almost identical to that of standard tissue-based genotyping. In contrast, plasma cfDNA-based liquid biopsy (n = 110) demonstrated sensitivity, specificity, and concordance rates of 48.5%, 86.3%, and 63.6%, respectively. The mean turn-around time of BALF liquid biopsy was significantly shorter (2.6 days) than that of tissue-based genotyping (13.9 days; p < 0.001). Therefore, the use of EV-based BALF shortens the time for confirmation of EGFR mutation status for starting EGFR-TKI treatment and can hence potentially improve clinical outcomes. As a result, we suggest that EV-based BALF EGFR testing in advanced lung NSCLC is a highly accurate rapid method and can be used as an alternative method for lung tissue biopsy.
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Affiliation(s)
- In Ae Kim
- Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul 05030, Korea; (I.A.K.); (J.Y.H.); (H.J.K.); (W.S.K.)
| | - Jae Young Hur
- Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul 05030, Korea; (I.A.K.); (J.Y.H.); (H.J.K.); (W.S.K.)
- Department of Pulmonary Medicine, Konkuk University School of Medicine, Seoul 05030, Korea
| | - Hee Joung Kim
- Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul 05030, Korea; (I.A.K.); (J.Y.H.); (H.J.K.); (W.S.K.)
- Department of Pathology, Konkuk University School of Medicine, Seoul 05030, Korea
| | - Wan Seop Kim
- Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul 05030, Korea; (I.A.K.); (J.Y.H.); (H.J.K.); (W.S.K.)
- Department of Pulmonary Medicine, Konkuk University School of Medicine, Seoul 05030, Korea
| | - Kye Young Lee
- Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul 05030, Korea; (I.A.K.); (J.Y.H.); (H.J.K.); (W.S.K.)
- Department of Pathology, Konkuk University School of Medicine, Seoul 05030, Korea
- Exosignal, Inc., Seoul 05030, Korea
- Correspondence: ; Tel.: +82-2-2030-7784
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Matsuzaka Y, Yashiro R. Immune Modulation Using Extracellular Vesicles Encapsulated with MicroRNAs as Novel Drug Delivery Systems. Int J Mol Sci 2022; 23:ijms23105658. [PMID: 35628473 PMCID: PMC9146104 DOI: 10.3390/ijms23105658] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/17/2022] [Accepted: 05/17/2022] [Indexed: 12/13/2022] Open
Abstract
Self-tolerance involves protection from self-reactive B and T cells via negative selection during differentiation, programmed cell death, and inhibition of regulatory T cells. The breakdown of immune tolerance triggers various autoimmune diseases, owing to a lack of distinction between self-antigens and non-self-antigens. Exosomes are non-particles that are approximately 50–130 nm in diameter. Extracellular vesicles can be used for in vivo cell-free transmission to enable intracellular delivery of proteins and nucleic acids, including microRNAs (miRNAs). miRNAs encapsulated in exosomes can regulate the molecular pathways involved in the immune response through post-transcriptional regulation. Herein, we sought to summarize and review the molecular mechanisms whereby exosomal miRNAs modulate the expression of genes involved in the immune response.
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Affiliation(s)
- Yasunari Matsuzaka
- Division of Molecular and Medical Genetics, Center for Gene and Cell Therapy, The Institute of Medical Science, University of Tokyo, Minato-ku 108-8639, Tokyo, Japan
- Correspondence: ; Tel.: +81-3-5449-5372
| | - Ryu Yashiro
- Administrative Section of Radiation Protection, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira 187-8551, Tokyo, Japan; or
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Li X, Li X, Zhang B, He B. The Role of Cancer Stem Cell-Derived Exosomes in Cancer Progression. Stem Cells Int 2022; 2022:9133658. [PMID: 35571530 PMCID: PMC9095362 DOI: 10.1155/2022/9133658] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 04/15/2022] [Indexed: 12/14/2022] Open
Abstract
Cancer stem cells (CSCs) represent a small portion of tumor cells with self-renewal ability in tumor tissues and are a key factor in tumor resistance, recurrence, and metastasis. CSCs produce a large number of exosomes through various mechanisms, such as paracrine and autocrine signaling. Studies have shown that CSC-derived exosomes (CSC-Exos) carry a variety of gene mutations and specific epigenetic modifications indicative of unique cell phenotypes and metabolic pathways, enabling exchange of information in the tumor microenvironment (TME) to promote tumor invasion and metastasis. In addition, CSC-Exos carry a variety of metabolites, especially proteins and miRNAs, which can activate signaling pathways to further promote tumor development. CSC-Exos have dual effects on cancer development. Due to advances in liquid biopsy technology for early cancer detection, CSCs-Exos may become an important tool for early cancer diagnosis and therapeutic drug delivery. In this article, we will review how CSC-Exos exert the above effects based on the above two aspects and explore their mechanism of action.
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Affiliation(s)
- Xueting Li
- Department of Clinical Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
| | - Xinjian Li
- Department of Nephrology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Bin Zhang
- Department of Clinical Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
| | - Baoyu He
- Department of Clinical Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
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Pirisinu M, Pham TC, Zhang DX, Hong TN, Nguyen LT, Le MT. Extracellular vesicles as natural therapeutic agents and innate drug delivery systems for cancer treatment: Recent advances, current obstacles, and challenges for clinical translation. Semin Cancer Biol 2022; 80:340-355. [PMID: 32977006 DOI: 10.1016/j.semcancer.2020.08.007] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 08/11/2020] [Accepted: 08/12/2020] [Indexed: 12/13/2022]
Abstract
As cancer poses a significant threat to the well-being of humans on a global scale, many researchers have embarked on the search for effective anticancer therapeutic agents. In recent years, many drugs have been shown to have extraordinary anticancer effects. However, in a lot of cases the treatment is accompanied by undesirable side effects due to some intrinsic properties linked to the therapeutic agents, such as poor targeting selectivity and short half-life in the circulation. In this regard, extracellular vesicles (EVs), a diverse family of natural cell-derived vesicles, steal the show as potential anticancer immunotherapy or delivery vectors of anticancer agents since they are an innate mechanism of intercellular communication. Here, we describe some of the most hotly-debated issues regarding the use of EVs as anticancer therapeutics. First, we review the biology of EVs providing the most up-to-date definition of EVs as well as highlighting their circulation kinetics and homing properties. Next, we share our views on popular methods reported for EV isolation, characterization, and functional analysis. Pioneering and innovative reports along with emerging challenges in the field of EV imaging and EV drug loading strategies are then discussed. Finally, we examine in detail the therapeutic application of EVs in cancer treatment, including their role in cancer immunotherapy and as natural delivery systems for anticancer agents including natural compounds such as paclitaxel and doxorubicin. We consider standardised protocols and proper analytical approaches to be crucial in improving the reproducibility and rigor in EV research and ensuring the successful translation of EVs as anticancer therapeutics.
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Affiliation(s)
- Marco Pirisinu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Department of Biomedical Sciences, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong SAR of China, China
| | - Tin Chanh Pham
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Department of Biomedical Sciences, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong SAR of China, China
| | - Daniel Xin Zhang
- Department of Biomedical Sciences, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong SAR of China, China; Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
| | - Tran Nguyen Hong
- Department of Pharmacology and Biochemistry, Vietnam Institute of Medicinal Materials, Hanoi, Vietnam
| | - Lap Thi Nguyen
- Department of Biochemistry, Hanoi University of Pharmacy, Hanoi, Vietnam
| | - Minh Tn Le
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Department of Biomedical Sciences, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong SAR of China, China.
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Tai J, Fan S, Ding S, Ren L. Gold Nanoparticles Based Optical Biosensors for Cancer Biomarker Proteins: A Review of the Current Practices. Front Bioeng Biotechnol 2022; 10:877193. [PMID: 35557858 PMCID: PMC9089302 DOI: 10.3389/fbioe.2022.877193] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 03/30/2022] [Indexed: 12/12/2022] Open
Abstract
Cancer prognosis depends on the early detection of the disease. Gold nanoparticles (AuNPs) have attracted much importance in biomedical research due to their distinctive optical properties. The AuNPs are easy to fabricate, biocompatible, surface controlled, stable, and have surface plasmonic properties. The AuNPs based optical biosensors can intensely improve the sensitivity, specificity, resolution, penetration depth, contrast, and speed of these devices. The key optical features of the AuNPs based biosensors include localized surface plasmon resonance (LSPR), SERS, and luminescence. AuNPs based biomarkers have the potential to sense the protein biomarkers at a low detection level. In this review, the fabrication techniques of the AuNPs have been reviewed. The optical biosensors based on LSPR, SERS, and luminescence are also evaluated. The application of these biosensors for cancer protein detection is discussed. Distinct examples of cancer research that have a substantial impact on both scientific and clinical research are presented.
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Affiliation(s)
- Jinghua Tai
- Department of Gastroenterology, the Second Hospital of Jilin University, Changchun, China
| | - Shuang Fan
- Department of Gastroenterology, the Second Hospital of Jilin University, Changchun, China
| | - Siqi Ding
- Department of Gastroenterology, the Second Hospital of Jilin University, Changchun, China
| | - Lishen Ren
- Department of Hematology and Oncology, The Second Hospital of Jilin University, Changchun, China
- *Correspondence: Lishen Ren,
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Lei H, Ma Y, Zhang H, Cao Z, Zhang H. Allosteric Probe Recognition Initiated Cascade Transcription Amplification for Sensitive Analysis of Exosomes. Chembiochem 2022; 23:e202200067. [PMID: 35315567 DOI: 10.1002/cbic.202200067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/12/2022] [Indexed: 11/06/2022]
Abstract
Sensitive and accurate analysis of exosome plays considerable roles in multifarious biological processes and being deemed to be important biomarkers for cerebral venous thrombosis (CVT) diagnosis and therapy. Herein, we established a sensitive and specific exosomes detection approach based on target recognition initiated cascade signal amplification. In this method, allosteric probe is designed with hairpin structure for specific recognition of exosome and inducing the following signal amplification. Eventually, generated spinach RNA sequences after the cascade signal amplification process bind to DFHBI ((Z)-4-(3,5-difluoro-4-hydroxybenzylidene)-1,2-dimethyl-1H-imidazol-5(4H)-one) to produce enhanced fluorescence signal (approximate 2000 fold than that of inactive DFHBI). Compared with former proposed exosomes detection methods, the method exhibited a comparable detection range, but with an easy-to-design toolbox. Therefore, we believe that the proposed approach holds great potential for exosome based early diagnosis and prognosis of disease.
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Affiliation(s)
- Huabin Lei
- Sun Simiao hospital, Department of Encephalopathy, CHINA
| | - Yaru Ma
- Sun Simiao hospital, Department of Encephalopathy, CHINA
| | - Hui Zhang
- Sun Simiao hospital, Department of Encephalopathy, CHINA
| | - Zenghui Cao
- Urumqi maternal and child health care hospital, Xinjiang human sperm bank, CHINA
| | - Heng Zhang
- sunsimiao hospital, department of clinical laboratory, Tongchuan, 727031, Tongchuan, CHINA
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Bowers EC, Motta A, Knox K, McKay BS, Ramos KS. LINE-1 Cargo and Reverse Transcriptase Activity Profiles in Extracellular Vesicles from Lung Cancer Cells and Human Plasma. Int J Mol Sci 2022; 23:ijms23073461. [PMID: 35408821 PMCID: PMC8998977 DOI: 10.3390/ijms23073461] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/17/2022] [Accepted: 03/21/2022] [Indexed: 01/08/2023] Open
Abstract
Long Interspersed Element-1 (LINE-1) is an oncogenic human retrotransposon that ‘copies and pastes’ DNA into new locations via reverse transcription. Given that enzymatically active LINE-1 can be exported in extracellular vesicles (EVs), and that LINE-1 mRNA and its two encoded proteins, ORF1p and ORF2p, are required for retrotransposition, the present study examined LINE-1 EV loading patterns relative to reverse transcriptase (RT) activity in vivo and in vitro. Density gradient ultracentrifugation identified conserved patterns of LINE-1 mRNA and protein distribution in EVs, with RT activity readily detected in EV fractions containing both LINE-1 mRNA and protein. Unlike whole cell and tissue lysates, the ORF1p in EVs was detected as a dimer. EVs from ostensibly healthy plasma donors showed variable but consistent ORF1p profiles, with residual levels of LINE-1 mRNA measured in some but not all samples. EVs from cancer cell lines had elevated mean LINE-1 levels and 5–85 times greater RT activity than EVs from normal cells or healthy plasma. EV RT activity was associated with EV LINE-1 mRNA content and was highest in cell lines that also expressed an elevated expression of ORF1p and ORF2p. Given that LINE-1 activation is a hallmark of many cancer types, our findings suggest that an EV LINE-1 ‘liquid biopsy’ may be developed to monitor LINE-1 activity during the course of malignant progression.
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Affiliation(s)
- Emma C. Bowers
- Center for Genomic and Precision Medicine, Texas A&M Institute of Biosciences and Technology, Houston, TX 77030, USA;
| | - Alexandre Motta
- University of Arizona College of Medicine-Tucson, Tucson, AZ 85724, USA;
| | - Ken Knox
- Department of Internal Medicine, Division of Pulmonary Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA;
| | - Brian S. McKay
- Department of Ophthalmology and Vision Science, University of Arizona College of Medicine-Tucson, Tucson, AZ 85724, USA;
| | - Kenneth S. Ramos
- Center for Genomic and Precision Medicine, Texas A&M Institute of Biosciences and Technology, Houston, TX 77030, USA;
- Correspondence: ; Tel.: +1-713-677-7760
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Wang W, Hao LP, Song H, Chu XY, Wang R. The Potential Roles of Exosomal Non-Coding RNAs in Hepatocellular Carcinoma. Front Oncol 2022; 12:790916. [PMID: 35280805 PMCID: PMC8912917 DOI: 10.3389/fonc.2022.790916] [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: 10/07/2021] [Accepted: 01/26/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth highest-incidence cancer and the 4th most deadly cancer all over the world, with a high fatality and low diagnostic rate. Nowadays, Excessive alcohol consumption, type-2 diabetes, smoking and obesity have become some primary risk factors of HCC. As intercellular messenger transporting information cargoes between cells, exosomes are a type of extracellular vesicles (EVs) released by most types of cells including tumor cells and non-tumor cells and play a pivotal role in establishing an HCC microenvironment. Exosomes, and more generally EVs, contain different molecules, including messenger RNAs (mRNAs), non-coding RNAs (ncRNAs), proteins, lipids and transcription factors. The three main ncRNAs in exosomes are microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs). NcRNAs, identified as essential components, are selectively sorted into exosomes and exosomal ncRNAs show great potential in regulating tumor development, including proliferation, invasion, angiogenesis, metastasis, immune escape and drug resistance. Here, we chiefly review the formation and uptake of exosomes, classification of exosomal ncRNAs and current research on the roles of exosomal ncRNAs in HCC progression. We also explored their clinical applications as new diagnostic biomarkers and therapeutic avenues in HCC.
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Affiliation(s)
- Wei Wang
- Department of Medical Oncology, Jinling Hospital, Nanjing Medical University, Nanjing, China
| | - Li-Ping Hao
- Department of Medical Oncology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China
| | - Haizhu Song
- Department of Medical Oncology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China
| | - Xiao-Yuan Chu
- Department of Medical Oncology, Jinling Hospital, Nanjing Medical University, Nanjing, China.,Department of Medical Oncology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China
| | - Rui Wang
- Department of Medical Oncology, Jinling Hospital, Nanjing Medical University, Nanjing, China.,Department of Medical Oncology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China
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Deng Y, Xue R, Patel N, Xu W, Zhang H. Serum Extracellular Nano-Vesicles miR-153-3p to Identify Micronodular Lung Cancer from Sub-Centimeter Lung Nodules. J Biomed Nanotechnol 2022; 18:705-717. [PMID: 35715903 DOI: 10.1166/jbn.2022.3292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Identification of malignancy from sub-centimeter lung nodules (LNs, <1 cm) is core for prevention and treatment of primary phases of lung cancer (LC). The study's purpose was to predict micro-nodular lung cancer (mnLC), such as adenocarcinoma in situ (AIS), micro-invasive adenocarcinoma (MIA), and invasive adenocarcinoma stage 1 (IA1) based on serum extracellular nano-vesicles (sEVs) miR-153-3p. sEVs-miR-153-3p was selected in this study and then used to investigate the expression and efficacy by RT-qPCR in the validation phase, followed by sEVs derived from patients of mnLC, benign lung nodule (BLN), and healthy people groups comprised of 135 recruiters. Further, the study established the prediction model which combined sEVs-miR-153-3p expression with multiple clinical-radiomics features by Logistic algorithms and was authenticated by the area under curve (AUC) phenomenon. Then, a simple-to-use nomogram was developed by Cox proportional-hazards regression modeling for predicting mnLC. Besides, in vitro analyses were performed to demonstrate miR-153-3p/ROCK1 axis in regulating biological mechanisms using LC cell lines. Results demonstrated that sEVs-miR-153-5p's expression values were higher in mnLC patients compared to BLN and healthy people. The prediction model for mnLC was successfully established, utilizing sEVs-miR-153-5p biomarker with significant clinical-radiomics features and yielding an AUC = 0.943 (95%CI: 0.898~0.989, P <0.0001). Moreover, the miR-153-3p and its targeted gene ROCK1 were confirmed as down-regulated in NSCLC cell lines and up-regulated expression respectively. Moreover, the miR-153-3p/ROCK1 axis took part in promoting the epithelial-mesenchymal transition (EMT) signaling pathway and regulated certain biological functions, such as proliferation, migration and invasion of LC cells. Therefore, the sEVs-miR-153-3p associated with radiomics-clinical features showed enormous potential to non-invasively identify malignancy from subcentimeter LNs. miR-153-3p could promote the genesis and progress of LC via EMT signaling pathway, which may serve as a therapeutic target.
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Affiliation(s)
- Yuxia Deng
- Department of Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, P. R. China
| | - Rongyu Xue
- Department of Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, P. R. China
| | - Nishant Patel
- Department of Cardiothoracic Surgery, Children's Hospital of Nanjing Medical University, Nanjing, 210008, P. R. China
| | - Wenwen Xu
- Department of Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, P. R. China
| | - Haijun Zhang
- Department of Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, P. R. China
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