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Zhang L, Wong CY, Shao H. Integrated technologies for molecular profiling of genetic and modified biomarkers in extracellular vesicles. LAB ON A CHIP 2025; 25:2504-2520. [PMID: 40135945 DOI: 10.1039/d5lc00053j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/27/2025]
Abstract
Extracellular vesicles (EVs) are nanoscale membrane vesicles actively released by cells into a variety of biofluids. EVs carry myriad molecular cargoes; these include classical genetic biomarkers inherited from the parent cells as well as EV modifications by other entities (e.g., small molecule drugs). Aided by these diverse cargoes, EVs enable long-distance intercellular communication and have been directly implicated in various disease pathologies. As such, EVs are being increasingly recognized as a source of valuable biomarkers for minimally-invasive disease diagnostics and prognostics. Despite the clinical potential, EV molecular profiling remains challenging, especially in clinical settings. Due to the nanoscale dimension of EVs as well as the abundance of contaminants in biofluids, conventional EV detection methods have limited resolution, require extensive sample processing and can lose rare biomarkers. To address these challenges, new micro- and nanotechnologies have been developed to discover EV biomarkers and empower clinical applications. In this review, we introduce EV biogenesis for different cargo incorporation, and discuss the use of various EV biomarkers for clinical applications. We also assess different chip-based integrated technologies developed to measure genetic and modified biomarkers in EVs. Finally, we highlight future opportunities in technology development to facilitate the clinical translation of various EV biomarkers.
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Affiliation(s)
- Li Zhang
- Institute for Health Innovation & Technology, National University of Singapore, MD6, 14 Medical Drive #14-01, Singapore 117599, Singapore.
| | - Chi Yan Wong
- Institute for Health Innovation & Technology, National University of Singapore, MD6, 14 Medical Drive #14-01, Singapore 117599, Singapore.
| | - Huilin Shao
- Institute for Health Innovation & Technology, National University of Singapore, MD6, 14 Medical Drive #14-01, Singapore 117599, Singapore.
- Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore 117583, Singapore
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
- Department of Materials Science and Engineering, College of Design and Engineering, National University of Singapore, Singapore 117575, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673, Singapore
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Wang X, Liu Y, Jiang Y, Li Q. Tumor-derived exosomes as promising tools for cancer diagnosis and therapy. Front Pharmacol 2025; 16:1596217. [PMID: 40444049 PMCID: PMC12119533 DOI: 10.3389/fphar.2025.1596217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Accepted: 05/06/2025] [Indexed: 06/02/2025] Open
Abstract
Mounting evidences indicated that cancer cell-derived exosomes (TDEs) contribute to cancer progression and metastasis by reshaping the tumor microenvironment (TME) and interfering immunity response. TDEs contain unique biomolecular cargo, consisting of protein, nucleic acid, and lipids. In recent years, TDEs have been used as potential disease therapeutics and diagnosis biomarkers and prime candidates as delivery tools for cancer treatment. In the present review, we firstly summarized TDEs biogenesis and characteristic. Also, the role of TDEs in cancer cell metastasis and invasiveness, drug resistance, and immunosuppression was mentioned via cell-cell communication. Additionally, we concluded the current strategies for TDE-based cancer therapy, including TDEs inhibition and clearance, usage as therapeutic drug delivery vector and cancer vaccines. Furthermore, combination therapy with engineered TDEs were summarized, such as radiotherapy, photodynamic therapy, photothermal therapy, and sonodynamic therapy. Consequently, the above opens up novel and interesting opportunities for cancer diagnosis and prognosis based on TDEs, which is prospective to accelerate the clinical translation of TDEs for cancer therapy.
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Affiliation(s)
- Xirui Wang
- Department of Biomedical Engineering, School of Medical Imaging Xuzhou Medical University, Xuzhou, China
| | - Yanfang Liu
- Department of Central Laboratory, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China
| | - Yaowen Jiang
- Department of Biomedical Engineering, School of Medical Imaging Xuzhou Medical University, Xuzhou, China
| | - Qinghua Li
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang, China
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Gu L, Shen Z, Shen S, Wang C, Liu Y, Wei X, Zheng M, Gu J, Chen X, Sun Y, Xu J, Lu Y, Lu W. The INAVA mRNA in Extracellular Vesicles Activates Normal Ovarian Fibroblasts by Phosphorylation-Ubiquitylation Crosstalk of HMGA2. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2500912. [PMID: 40265981 DOI: 10.1002/advs.202500912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Indexed: 04/24/2025]
Abstract
Ovarian cancer is an aggressive gynecological tumor usually diagnosed with widespread metastases. Extracellular vesicles (EVs), though recognized as important mediators of tumor metastasis, have received limited attention into their specific functions via the mRNA profiling. Here it is reported elevated expression and selective enrichment of INAVA mRNA in both plasma- and tissue-derived EVs from ovarian cancer patients, which is positively correlated with distant metastasis and poor prognosis. Functionally, INAVA mRNA, upon uptake and translation, activates normal ovarian fibroblasts (NOFs) and drives extensive peritoneum metastasis in the orthotopic xenograft mouse model. Mechanistically, INAVA competitively binds with high mobility group protein A2 (HMGA2) and consequently inhibit its interaction with vaccinia-related kinase 1 (VRK1), leading to reduced HMGA2 phosphorylation on Ser105. Interestingly, this inhibitory phosphorylation stabilizes HMGA2 via blocking tripartite motif-containing 21 (TRIM21) -mediated K48-linked ubiquitylation, and ultimately enhances the transcription of STAT3 to activate NOFs. Lastly, a cell-permeable peptide that disrupts the INAVA-HMGA2 interaction leads to attenuated NOF activation and provides a promising strategy for ovarian cancer therapy.
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Affiliation(s)
- Lingkai Gu
- Zhejiang Key Laboratory of Maternal and Infant Health, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Zhangjin Shen
- Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China
| | - Shizhen Shen
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Conghui Wang
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Yuwan Liu
- Zhejiang Key Laboratory of Maternal and Infant Health, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Xinyi Wei
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Mengxia Zheng
- Zhejiang Key Laboratory of Maternal and Infant Health, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Jiaxin Gu
- Zhejiang Key Laboratory of Maternal and Infant Health, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Xiaojing Chen
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Yi Sun
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310029, China
- Cancer Center, Zhejiang University, Hangzhou, 310058, China
- Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, 310009, China
- Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou, 310053, China
| | - Junfen Xu
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Yan Lu
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310029, China
- Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310029, China
| | - Weiguo Lu
- Zhejiang Key Laboratory of Maternal and Infant Health, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
- Cancer Center, Zhejiang University, Hangzhou, 310058, China
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, 310006, China
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Izadi N, Solár P, Hašanová K, Zamani A, Akbar MS, Mrázová K, Bartošík M, Kazda T, Hrstka R, Joukal M. Breaking boundaries: role of the brain barriers in metastatic process. Fluids Barriers CNS 2025; 22:3. [PMID: 39780275 PMCID: PMC11708195 DOI: 10.1186/s12987-025-00618-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 01/02/2025] [Indexed: 01/11/2025] Open
Abstract
Brain metastases (BMs) are the most common intracranial tumors in adults and occur 3-10 times more frequently than primary brain tumors. Despite intensive multimodal therapies, including resection, radiotherapy, and chemotherapy, BMs are associated with poor prognosis and remain challenging to treat. BMs predominantly originate from primary lung (20-56%), breast (5-20%), and melanoma (7-16%) tumors, although they can arise from other cancer types less frequently. The metastatic cascade is a multistep process involving local invasion, intravasation into the bloodstream or lymphatic system, extravasation into normal tissue, and colonization of the distal site. After reaching the brain, circulating tumor cells (CTCs) breach the blood-brain barrier (BBB).The selective permeability of the BBB poses a significant challenge for therapeutic compounds, limiting the treatment efficacy of BMs. Understanding the mechanisms of tumor cell interactions with the BBB is crucial for the development of effective treatments. This review provides an in-depth analysis of the brain barriers, including the BBB, blood-spinal cord barrier, blood-meningeal barrier, blood-arachnoid barrier, and blood-cerebrospinal fluid barrier. It explores the molecular and cellular components of these barriers and their roles in brain metastasis, highlighting the importance of this knowledge for identifying druggable targets to prevent or limit BM formation.
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Affiliation(s)
- Nasim Izadi
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty Kopec 7, 656 53, Brno, Czech Republic
| | - Peter Solár
- Department of Anatomy, Cellular and Molecular Neurobiology Research Group, Faculty of Medicine, Masaryk University, 625 00, Brno, Czech Republic
- Department of Neurosurgery, Faculty of Medicine, Masaryk University, St Anne University Hospital Brno, Pekařská 53, 656 91, Brno, Czech Republic
| | - Klaudia Hašanová
- Department of Anatomy, Cellular and Molecular Neurobiology Research Group, Faculty of Medicine, Masaryk University, 625 00, Brno, Czech Republic
| | - Alemeh Zamani
- Department of Anatomy, Cellular and Molecular Neurobiology Research Group, Faculty of Medicine, Masaryk University, 625 00, Brno, Czech Republic
| | - Maryam Shahidian Akbar
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty Kopec 7, 656 53, Brno, Czech Republic
| | - Klára Mrázová
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty Kopec 7, 656 53, Brno, Czech Republic
| | - Martin Bartošík
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty Kopec 7, 656 53, Brno, Czech Republic
| | - Tomáš Kazda
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty Kopec 7, 656 53, Brno, Czech Republic
| | - Roman Hrstka
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty Kopec 7, 656 53, Brno, Czech Republic.
| | - Marek Joukal
- Department of Anatomy, Cellular and Molecular Neurobiology Research Group, Faculty of Medicine, Masaryk University, 625 00, Brno, Czech Republic.
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Tripathi S, Sharma Y, Kumar D. Biological Cargo: Exosomes and their Role in Cancer Progression and Metastasis. Curr Top Med Chem 2025; 25:263-285. [PMID: 38984577 DOI: 10.2174/0115680266304636240626055711] [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: 01/16/2024] [Revised: 05/23/2024] [Accepted: 05/23/2024] [Indexed: 07/11/2024]
Abstract
Cancer cells are among the many types of cells that release exosomes, which are nanovesicles. Because of their many potential applications, exosomes have recently garnered much attention from cancer researchers. The bioactive substances that exosomes release as cargo have been the subject of several investigations. The substances in question may operate as biomarkers for diagnosis or affect apoptosis, the immune system, the development and spread of cancer, and other processes. Others have begun to look at exosomes in experimental therapeutic trials because they believe they may be useful in the treatment of cancer. This review started with a short description of exosome biogenesis and key features. Next, the potential of tumor-derived exosomes and oncosomes to influence the immune system throughout the development of cancer, as well as alter tumor microenvironments (TMEs) and pre-metastatic niche creation, was investigated. Finally, there was talk of exosomes' possible use in cancer treatment. Furthermore, there is emerging consensus about the potential application of exosomes to be biological reprogrammers of cancer cells, either as carriers of naturally occurring chemicals, including anticancer medications, or as carriers of anticancer vaccines for immunotherapy as well as boron neutron capture therapy (BNCT). We briefly review the key ideas and logic behind this intriguing therapy recommendation.
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Affiliation(s)
- Siddhant Tripathi
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India
| | - Yashika Sharma
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India
| | - Dileep Kumar
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India
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Inubushi S, Kunihisa T, Kuniyasu M, Inoue S, Yamamoto M, Yamashita Y, Miki M, Mizumoto S, Baba M, Hoffman RM, Tanino H. Serum Exosomes Expressing CD9, CD63 and HER2 From Breast-Cancer Patients Decreased After Surgery of the Primary Tumor: A Potential Biomarker of Tumor Burden. Cancer Genomics Proteomics 2024; 21:580-584. [PMID: 39467625 PMCID: PMC11534029 DOI: 10.21873/cgp.20474] [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: 06/21/2024] [Revised: 07/23/2024] [Accepted: 08/18/2024] [Indexed: 10/30/2024] Open
Abstract
BACKGROUND/AIM Exosomes are extracellular vesicles produced by both normal and cancer cells. Previous research has demonstrated that circulating exosomes derived from cancer cells may create a niche for future metastasis, distant from the primary tumor. In the present report, circulating exosomes were captured and quantified based on exosome-surface proteins in pre- and post-operative serum of breast cancer patients, focusing on the exosome markers CD9 and CD63, as well as HER2, a therapeutic target for breast cancer. MATERIALS AND METHODS Eight breast cancer patients were recruited, and their pre- and post-operative serum samples were analyzed for CD63 and CD9; or CD9 and human epidermal growth factor receptor-2 (HER2), double-positive exosomes. An ExoCounter with antibody-conjugated beads was used to capture serum-derived exosomes. Sera from patients with tumors larger than 10 mm were used for analysis. The resected breast cancer was also histopathologically analyzed for the presence of HER2. RESULTS CD63 and CD9 double-positive serum exosomes and CD9 and HER2 double-positive serum exosomes decreased after surgery in breast-cancer patients whose tumors expressed HER2, as determined by histopathological analysis. CONCLUSION Serum exosomes expressing CD9, CD63 and HER2 are candidate biomarkers of tumor burden in HER2-positive breast-cancer patients.
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Affiliation(s)
- Sachiko Inubushi
- Division of Breast and Endocrine Surgery, Graduate School of Medicine, Kobe University, Hyogo, Japan
| | - Tomonari Kunihisa
- Division of Breast and Endocrine Surgery, Graduate School of Medicine, Kobe University, Hyogo, Japan
| | - Marina Kuniyasu
- Division of Breast and Endocrine Surgery, Graduate School of Medicine, Kobe University, Hyogo, Japan
| | - Shotaro Inoue
- Division of Breast and Endocrine Surgery, Graduate School of Medicine, Kobe University, Hyogo, Japan
| | - Mayuko Yamamoto
- Division of Breast and Endocrine Surgery, Graduate School of Medicine, Kobe University, Hyogo, Japan
| | - Yuji Yamashita
- Division of Breast and Endocrine Surgery, Graduate School of Medicine, Kobe University, Hyogo, Japan
| | - Mayuko Miki
- Division of Breast and Endocrine Surgery, Graduate School of Medicine, Kobe University, Hyogo, Japan
| | - Sachiko Mizumoto
- Division of Breast and Endocrine Surgery, Graduate School of Medicine, Kobe University, Hyogo, Japan
| | - Motoi Baba
- Division of Breast and Endocrine Surgery, Graduate School of Medicine, Kobe University, Hyogo, Japan
| | - Robert M Hoffman
- AntiCancer Inc, San Diego, CA, U.S.A
- Department of Surgery, University of California, San Diego, CA, U.S.A
| | - Hirokazu Tanino
- Department of Cardiovascular, Respiratory and Breast Surgery, Wakayama Medical University, Wakayama, Japan
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Yadav J, Chaudhary A, Tripathi T, Janjua D, Joshi U, Aggarwal N, Chhokar A, Keshavam CC, Senrung A, Bharti AC. Exosomal transcript cargo and functional correlation with HNSCC patients' survival. BMC Cancer 2024; 24:1144. [PMID: 39272022 PMCID: PMC11395213 DOI: 10.1186/s12885-024-12759-9] [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: 06/12/2024] [Accepted: 08/02/2024] [Indexed: 09/15/2024] Open
Abstract
BACKGROUND HPV status in a subset of HNSCC is linked with distinct treatment outcomes. Present investigation aims to elucidate the distinct clinicopathological features of HPV-positive and HPV-negative HNSCC and investigate their association with the HNSCC patient survival. MATERIALS AND METHODS The total RNA of exosomes from HPV-positive (93VU147T) and HPV-negative (OCT-1) HNSCC cells was isolated, and the transcripts were estimated using Illumina HiSeq X. The expression of altered transcripts and their clinical relevance were further analyzed using publicly available cancer transcriptome data from The Cancer Genome Atlas (TCGA). RESULTS Transcriptomic analyses identified 3785 differentially exported transcripts (DETs) in HPV-positive exosomes compared to HPV-negative exosomes. DETs that regulate the protein machinery, cellular redox potential, and various neurological disorder-related pathways were over-represented in HPV-positive exosomes. TCGA database revealed the clinical relevance of altered transcripts. Among commonly exported abundant transcripts, SGK1 and MAD1L1 showed high expression, which has been correlated with poor survival in HNSCC patients. In the top 20 DETs of HPV-negative exosomes, high expression of FADS3, SGK3, and TESK2 correlated with poor survival of the HNSCC patients in the TCGA database. CONCLUSION Overall, our study demonstrates that HPV-positive and HPV-negative cells' exosomes carried differential transcripts cargo that may be related to pathways associated with neurological disorders. Additionally, the altered transcripts identified have clinical relevance, correlating with patient survival in HNSCC, thereby highlighting their potential as biomarkers and as therapeutic targets.
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Affiliation(s)
- Joni Yadav
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
| | - Apoorva Chaudhary
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
| | - Tanya Tripathi
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
| | - Divya Janjua
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
| | - Udit Joshi
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
| | - Nikita Aggarwal
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
| | - Arun Chhokar
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
- Department of Zoology, Deshbandhu College, University of Delhi, Delhi, India
| | - Chetkar Chandra Keshavam
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
| | - Anna Senrung
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
- Department of Zoology, Daulat Ram College, University of Delhi, Delhi, India
| | - Alok Chandra Bharti
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India.
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Niu Q, Lin C, Yang S, Rong S, Wei J, Zhao T, Peng Y, Cheng Z, Xie Y, Wang Y. FoxO1-Overexpressed Small Extracellular Vesicles Derived from hPDLSCs Promote Periodontal Tissue Regeneration by Reducing Mitochondrial Dysfunction to Regulate Osteogenesis and Inflammation. Int J Nanomedicine 2024; 19:8751-8768. [PMID: 39220194 PMCID: PMC11365494 DOI: 10.2147/ijn.s470419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 08/18/2024] [Indexed: 09/04/2024] Open
Abstract
Purpose Periodontitis is a chronic infectious disease characterized by progressive inflammation and alveolar bone loss. Forkhead box O1 (FoxO1), an important regulator, plays a crucial role in maintaining bone homeostasis and regulating macrophage energy metabolism and osteogenic differentiation of mesenchymal stem cells (MSCs). In this study, FoxO1 was overexpressed into small extracellular vesicles (sEV) using engineering technology, and effects of FoxO1-overexpressed sEV on periodontal tissue regeneration as well as the underlying mechanisms were investigated. Methods Human periodontal ligament stem cell (hPDLSCs)-derived sEV (hPDLSCs-sEV) were isolated using ultracentrifugation. They were then characterized using transmission electron microscopy, Nanosight, and Western blotting analyses. hPDLSCs were treated with hPDLSCs-sEV in vitro after stimulation with lipopolysaccharide, and osteogenesis was evaluated. The effect of hPDLSCs-sEV on the polarization phenotype of THP-1 macrophages was also evaluated. In addition, we measured the reactive oxygen species (ROS) levels, adenosine triphosphate (ATP) production, mitochondrial characteristics, and metabolism of hPDLSCs and THP-1 cells. Experimental periodontitis was established in vivo in mice. HPDLSCs-sEV or phosphate-buffered saline (PBS) were injected into periodontal tissues for four weeks, and the maxillae were collected and assessed by micro-computed tomography, histological staining, and small animal in vivo imaging. Results In vitro, FoxO1-overexpressed sEV promoted osteogenic differentiation of hPDLSCs in the inflammatory environment and polarized THP-1 cells from the M1 phenotype to the M2 phenotype. Furthermore, FoxO1-overexpressed sEV regulated the ROS level, ATP production, mitochondrial characteristics, and metabolism of hPDLSCs and THP-1 cells in the inflammatory environment. In the in vivo analyses, FoxO1-overexpressed sEV effectively promoted bone formation and inhibited inflammation. Conclusion FoxO1-overexpressed sEV can regulate osteogenesis and immunomodulation. The ability of FoxO1-overexpressed sEV to regulate inflammation and osteogenesis can pave the way for the establishment of a therapeutic approach for periodontitis.
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Affiliation(s)
- Qingru Niu
- Hospital of Stomatology, Guanghua School of Stomatology, Guangzhou, People’s Republic of China
- Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People’s Republic of China
| | - Chuanmiao Lin
- Hospital of Stomatology, Guanghua School of Stomatology, Guangzhou, People’s Republic of China
- Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People’s Republic of China
| | - Shuqing Yang
- Hospital of Stomatology, Guanghua School of Stomatology, Guangzhou, People’s Republic of China
- Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People’s Republic of China
| | - Shuxuan Rong
- Hospital of Stomatology, Guanghua School of Stomatology, Guangzhou, People’s Republic of China
- Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People’s Republic of China
| | - Junbin Wei
- Hospital of Stomatology, Guanghua School of Stomatology, Guangzhou, People’s Republic of China
- Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People’s Republic of China
| | - Tingting Zhao
- Hospital of Stomatology, Guanghua School of Stomatology, Guangzhou, People’s Republic of China
- Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People’s Republic of China
| | - Yingying Peng
- Hospital of Stomatology, Guanghua School of Stomatology, Guangzhou, People’s Republic of China
- Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People’s Republic of China
| | - Zhilan Cheng
- Hospital of Stomatology, Guanghua School of Stomatology, Guangzhou, People’s Republic of China
- Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People’s Republic of China
| | - Yunyi Xie
- Hospital of Stomatology, Guanghua School of Stomatology, Guangzhou, People’s Republic of China
- Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People’s Republic of China
| | - Yan Wang
- Hospital of Stomatology, Guanghua School of Stomatology, Guangzhou, People’s Republic of China
- Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People’s Republic of China
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Ala U, Fagoonee S. RNA-binding protein transcripts as potential biomarkers for detecting Primary Sclerosing Cholangitis and for predicting its progression to Cholangiocarcinoma. Front Mol Biosci 2024; 11:1388294. [PMID: 38903178 PMCID: PMC11187294 DOI: 10.3389/fmolb.2024.1388294] [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: 02/19/2024] [Accepted: 05/13/2024] [Indexed: 06/22/2024] Open
Abstract
Primary Sclerosing Cholangitis (PSC) is a persistent inflammatory liver condition that affects the bile ducts and is commonly diagnosed in young individuals. Despite efforts to incorporate various clinical, biochemical and molecular parameters for diagnosing PSC, it remains challenging, and no biomarkers characteristic of the disease have been identified hitherto. PSC is linked with an uncertain prognosis, and there is a pressing need to explore multiomics databases to establish a new biomarker panel for the early detection of PSC's gradual progression into Cholangiocarcinoma (CCA) and for the development of effective therapeutic interventions. Apart from non-coding RNAs, other components of the Ribonucleoprotein (RNP) complex, such as RNA-Binding Proteins (RBPs), also hold great promise as biomarkers due to their versatile expression in pathological conditions. In the present review, an update on the RBP transcripts that show dysregulated expression in PSC and CCA is provided. Moreover, by utilizing a bioinformatic data mining approach, we give insight into those RBP transcripts that also exhibit differential expression in liver and gall bladder, as well as in body fluids, and are promising as biomarkers for diagnosing and predicting the prognosis of PSC. Expression data were bioinformatically extracted from public repositories usingTCGA Bile Duct Cancer dataset for CCA and specific NCBI GEO datasets for both PSC and CCA; more specifically, RBPs annotations were obtained from RBP World database. Interestingly, our comprehensive analysis shows an elevated expression of the non-canonical RBPs, FANCD2, as well as the microtubule dynamics regulator, ASPM, transcripts in the body fluids of patients with PSC and CCA compared with their respective controls, with the same trend in expression being observed in gall bladder and liver cancer tissues. Consequently, the manipulation of tissue expression of RBP transcripts might be considered as a strategy to mitigate the onset of CCA in PSC patients, and warrants further experimental investigation. The analysis performed herein may be helpful in the identification of non-invasive biomarkers for the early detection of PSC and for predicting its progression into CCA. In conclusion, future clinical research should investigate in more depth the full potential of RBP transcripts as biomarkers for human pathologies.
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Affiliation(s)
- Ugo Ala
- Department of Veterinary Sciences, University of Turin, Turin, Italy
| | - Sharmila Fagoonee
- Institute of Biostructure and Bioimaging (CNR), Molecular Biotechnology Center “Guido Tarone”, Turin, Italy
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10
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Tamraz M, Al Ghossaini N, Temraz S. The Role of Wheatgrass in Colorectal Cancer: A Review of the Current Evidence. Int J Mol Sci 2024; 25:5166. [PMID: 38791211 PMCID: PMC11121291 DOI: 10.3390/ijms25105166] [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: 03/23/2024] [Revised: 04/23/2024] [Accepted: 05/02/2024] [Indexed: 05/26/2024] Open
Abstract
The etiology of colon cancer is either genetic in nature or results from inflammatory bowel diseases such as ulcerative colitis and Crohn's disease; nevertheless, dietary habits play a crucial role in the disease. Wheatgrass is a dietary supplement that is rich in vitamins, minerals, and antioxidants which contribute to health promotion in cardiovascular diseases, liver disease, blood diseases, diabetes, and inflammatory bowel diseases, as well as in several types of cancers, such as oral squamous cell cancer, cervical cancer, and breast cancer. In colorectal cancer (CRC), the prospect that wheatgrass possesses anti-inflammatory, antioxidant, and anticancer properties, and its use as an adjunctive therapy, have been minimally investigated and evidence is still limited. In this review, we compiled the available evidence pertaining to wheatgrass and its likely impact on CRC, described the pathways of inflammation in which wheatgrass could possibly play a role, and identified future research needs on the subject.
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Affiliation(s)
- Magie Tamraz
- Department of Nutrition and Public Health, Holy Spirit University of Kaslik, Jounieh P.O. BOX 446, Mount Lebanon, Lebanon;
| | - Najib Al Ghossaini
- Department of Internal Medicine, Ain Wazein Medical Village, Chouf P.O. Box 1503-210/02, Mount Lebanon, Lebanon;
| | - Sally Temraz
- Department of Internal Medicine, Oncology/Hematology Division, American University of Beirut Medical Center, Riad El Solh, Beirut 1107 2020, Lebanon
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11
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Yimin E, Lu C, Zhu K, Li W, Sun J, Ji P, Meng M, Liu Z, Yu C. Function and mechanism of exosomes derived from different cells as communication mediators in colorectal cancer metastasis. iScience 2024; 27:109350. [PMID: 38500820 PMCID: PMC10945197 DOI: 10.1016/j.isci.2024.109350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2024] Open
Abstract
Colorectal cancer (CRC) ranks as the second leading cause of cancer-related mortality, with metastasis being the primary determinant of poor prognosis in patients. Investigating the molecular mechanisms underlying CRC metastasis is currently a prominent and challenging area of research. Exosomes, as crucial intercellular communication mediators, facilitate the transfer of metabolic and genetic information from cells of origin to recipient cells. Their roles in mediating information exchange between CRC cells and immune cells, fibroblasts, and other cell types are pivotal in reshaping the tumor microenvironment, regulating key biological processes such as invasion, migration, and formation of pre-metastatic niche. This article comprehensively examines the communication function and mechanism of exosomes derived from different cells in cancer metastasis, while also presenting an outlook on current research advancements and future application prospects. The aim is to offer a distinctive perspective that contributes to accurate diagnosis and rational treatment strategies for CRC.
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Affiliation(s)
- Yimin E
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiang Jia Yuan Road, Nanjing 210011, Jiangsu, China
| | - Chen Lu
- Department of General Surgery, Sir Run Run Hospital of Nanjing Medical University, Long Mian Avenue 109 Jiangning, Nanjing 211112, Jiangsu, China
| | - Kuixuan Zhu
- Department of Radiotherapy, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), Kunming 650100, Yunan, China
| | - Wenyuan Li
- Department of Anesthesiology, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiang Jia Yuan Road, Nanjing 210011, Jiangsu, China
| | - Jing Sun
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiang Jia Yuan Road, Nanjing 210011, Jiangsu, China
| | - Pengcheng Ji
- Department of General Surgery, Sir Run Run Hospital of Nanjing Medical University, Long Mian Avenue 109 Jiangning, Nanjing 211112, Jiangsu, China
| | - Minjie Meng
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiang Jia Yuan Road, Nanjing 210011, Jiangsu, China
| | - Zhengxia Liu
- Department of Geriatrics, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiang Jia Yuan Road, Nanjing 210011, Jiangsu, China
| | - Chunzhao Yu
- Department of General Surgery, Sir Run Run Hospital of Nanjing Medical University, Long Mian Avenue 109 Jiangning, Nanjing 211112, Jiangsu, China
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiang Jia Yuan Road, Nanjing 210011, Jiangsu, China
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12
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Pagani A, Duscher D, Geis S, Klein S, Knoedler L, Panayi AC, Oliinyk D, Felthaus O, Prantl L. The Triple Adipose-Derived Stem Cell Exosome Technology as a Potential Tool for Treating Triple-Negative Breast Cancer. Cells 2024; 13:614. [PMID: 38607053 PMCID: PMC11011929 DOI: 10.3390/cells13070614] [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: 03/05/2024] [Revised: 03/26/2024] [Accepted: 03/29/2024] [Indexed: 04/13/2024] Open
Abstract
BACKGROUND Extracellular vesicles are pivotal mediators in intercellular communication, facilitating the exchange of biological information among healthy, pathological and tumor cells. Between the diverse subtypes of extracellular vesicles, exosomes have unique properties and clinical and therapeutical applications. Breast cancer ranks as one of the most prevalent malignancies across the globe. Both the tumor core and its surrounding microenvironment engage in a complex, orchestrated interaction that facilitates cancer's growth and spread. METHODS The most significant PubMed literature about extracellular vesicles and Adipose-Derived Stem Cell Exosomes and breast cancer was selected in order to report their biological properties and potential applications, in particular in treating triple-negative breast cancer. RESULTS Adipose-Derived Stem Cell Exosomes represent a potential tool in targeting triple-negative breast cancer cells at three main levels: the tumor core, the tumor microenvironment and surrounding tissues, including metastases. CONCLUSIONS The possibility of impacting triple-negative breast cancer cells with engineered Adipose-Derived Stem Cell Exosomes is real. The opportunity to translate our current in vitro analyses into a future in vivo scenario is even more challenging.
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Affiliation(s)
- Andrea Pagani
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany (S.K.); (O.F.); (L.P.)
| | - Dominik Duscher
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany (S.K.); (O.F.); (L.P.)
| | - Sebastian Geis
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany (S.K.); (O.F.); (L.P.)
| | - Silvan Klein
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany (S.K.); (O.F.); (L.P.)
| | - Leonard Knoedler
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany (S.K.); (O.F.); (L.P.)
| | - Adriana C. Panayi
- Department of Plastic, Hand and Reconstructive Surgery, BG Klinik Ludwigshafen, University of Heidelberg, Ludwig-Guttmann-Straße 13, 67071 Ludwigshafen, Germany
| | - Dmytro Oliinyk
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany (S.K.); (O.F.); (L.P.)
| | - Oliver Felthaus
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany (S.K.); (O.F.); (L.P.)
| | - Lukas Prantl
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany (S.K.); (O.F.); (L.P.)
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13
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Yu L, Zeng X, Hu X, Wen Q, Chen P. Advances and challenges in clinical applications of tumor cell-derived extracellular vesicles. Colloids Surf B Biointerfaces 2024; 234:113704. [PMID: 38113751 DOI: 10.1016/j.colsurfb.2023.113704] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 12/05/2023] [Accepted: 12/07/2023] [Indexed: 12/21/2023]
Abstract
Extracellular vesicles (EVs) are a class of substances that feature vesicle-like structures. Initially deemed to be "biological waste", recent studies have highlighted the crucial role of EVs in mediating information communication between cells by transporting bioactive components. Specifically, tumor cell-derived extracellular vesicles (TEVs) contain components that can be utilized for disease diagnosis and as vaccines to activate the immune system. Moreover, since TEVs have a phospholipid bilayer shell and can transport exogenous substances, they are being increasingly explored as drug delivery vehicles in anti-tumor therapy. TEVs have proven highly compatible with their corresponding tumor cells, allowing for efficient drug delivery and exerting killing effects on tumor cells through various mechanisms such as domino effects, lysosomal pathways, and inhibition of drug efflux from tumor tissues. Despite these promising developments, challenges remain in the clinical applications of EVs derived from tumor cells. This paper outlines the current advances and limitations in this field, highlighting the potential of TEVs as a powerful tool for combating cancer.
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Affiliation(s)
- Li Yu
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Department of Oncology, Jiangsu Cancer Hospital, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210009, China
| | - Xiaonan Zeng
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Xiao Hu
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Department of Oncology, the Second Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Qinglian Wen
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Ping Chen
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.
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14
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Zhang N, Shu L, Liu Z, Shi A, Zhao L, Huang S, Sheng G, Yan Z, Song Y, Huang F, Tang Y, Zhang Z. The role of extracellular vesicles in cholangiocarcinoma tumor microenvironment. Front Pharmacol 2024; 14:1336685. [PMID: 38269274 PMCID: PMC10805838 DOI: 10.3389/fphar.2023.1336685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 12/26/2023] [Indexed: 01/26/2024] Open
Abstract
Cholangiocarcinoma (CCA) is a highly aggressive malignant tumor that originates from the biliary system. With restricted treatment options at hand, the challenging aspect of early CCA diagnosis leads to a bleak prognosis. Besides the intrinsic characteristics of tumor cells, the generation and progression of CCA are profoundly influenced by the tumor microenvironment, which engages in intricate interactions with cholangiocarcinoma cells. Of notable significance is the role of extracellular vesicles as key carriers in enabling communication between cancer cells and the tumor microenvironment. This review aims to provide a comprehensive overview of current research examining the interplay between extracellular vesicles and the tumor microenvironment in the context of CCA. Specifically, we will emphasize the significant contributions of extracellular vesicles in molding the CCA microenvironment and explore their potential applications in the diagnosis, prognosis assessment, and therapeutic strategies for this aggressive malignancy.
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Affiliation(s)
- Nuoqi Zhang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Lizhuang Shu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Zengli Liu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
- Department of General Surgery, Qilu Hospital, Shandong University, Qingdao, Shandong, China
| | - Anda Shi
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Liming Zhao
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Shaohui Huang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Guoli Sheng
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Zhangdi Yan
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Yan Song
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Fan Huang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Yongchang Tang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Zongli Zhang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
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15
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Wangmo D, Gates TJ, Zhao X, Sun R, Subramanian S. Centrosomal Protein 55 (CEP55) Drives Immune Exclusion and Resistance to Immune Checkpoint Inhibitors in Colorectal Cancer. Vaccines (Basel) 2024; 12:63. [PMID: 38250876 PMCID: PMC10820828 DOI: 10.3390/vaccines12010063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 01/02/2024] [Accepted: 01/05/2024] [Indexed: 01/23/2024] Open
Abstract
Colorectal cancer (CRC) currently ranks as the third most common cancer in the United States, and its incidence is on the rise, especially among younger individuals. Despite the remarkable success of immune checkpoint inhibitors (ICIs) in various cancers, most CRC patients fail to respond due to intrinsic resistance mechanisms. While microsatellite instability-high phenotypes serve as a reliable positive predictive biomarker for ICI treatment, the majority of CRC patients with microsatellite-stable (MSS) tumors remain ineligible for this therapeutic approach. In this study, we investigated the role of centrosomal protein 55 (CEP55) in shaping the tumor immune microenvironment in CRC. CEP55 is overexpressed in multiple cancer types and was shown to promote tumorigenesis by upregulating the PI3K/AKT pathway. Our data revealed that elevated CEP55 expression in CRC was associated with reduced T cell infiltration, contributing to immune exclusion. As CRC tumors progressed, CEP55 expression increased alongside sequential mutations in crucial driver genes (APC, KRAS, TP53, and SMAD4), indicating its involvement in tumor progression. CEP55 knockout significantly impaired tumor growth in vitro and in vivo, suggesting that CEP55 plays a crucial role in tumorigenesis. Furthermore, the CEP55 knockout increased CD8+ T cell infiltration and granzyme B production, indicating improved anti-tumor immunity. Additionally, we observed reduced regulatory T cell infiltration in CEP55 knockout tumors, suggesting diminished immune suppression. Most significantly, CEP55 knockout tumors demonstrated enhanced responsiveness to immune checkpoint inhibition in a clinically relevant orthotopic CRC model. Treatment with anti-PD1 significantly reduced tumor growth in CEP55 knockout tumors compared to control tumors, suggesting that inhibiting CEP55 could improve the efficacy of ICIs. Collectively, our study underscores the crucial role of CEP55 in driving immune exclusion and resistance to ICIs in CRC. Targeting CEP55 emerges as a promising therapeutic strategy to sensitize CRC to immune checkpoint inhibition, thereby improving survival outcomes for CRC patients.
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Affiliation(s)
- Dechen Wangmo
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA; (D.W.); (T.J.G.); (X.Z.)
- Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Travis J. Gates
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA; (D.W.); (T.J.G.); (X.Z.)
- Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Xianda Zhao
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA; (D.W.); (T.J.G.); (X.Z.)
| | - Ruping Sun
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA;
- Department of Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Subbaya Subramanian
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA; (D.W.); (T.J.G.); (X.Z.)
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA;
- Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA
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16
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Li X, Chang Y, Shen W, Huang G, Hu N, Lv H, Jin M. miR-138 from ADSC Exo accelerates wound healing by targeting SIRT1/PTEN pathway to promote angiogenesis and fibrosis. Cell Signal 2023; 111:110843. [PMID: 37544635 DOI: 10.1016/j.cellsig.2023.110843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/11/2023] [Accepted: 08/03/2023] [Indexed: 08/08/2023]
Affiliation(s)
- Xue Li
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Yuzhen Chang
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Weijun Shen
- Department of Anesthesiology, Tenth People's Hospital of Tongji University, No 301 Middle Yan Chang Road, Shanghai 200072, China
| | - Gang Huang
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.
| | - Nan Hu
- Department of Vascular Surgery, The Affiliated Nanjing Drum Tower Hospital, Nanjing University Medical School, 21000, Jiangsu, China.
| | - Haihong Lv
- Department of endocrinology, The First Hospital of Lanzhou University, #1 Donggang West Road Road, Lanzhou, 730000, Gansu, China.
| | - Mingming Jin
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.
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17
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Ahonen T, Ng CP, Farinha B, Almeida B, Victor BL, Reynolds C, Kalso E, Yli-Kauhaluoma J, Greaves J, Moreira VM. Probing the Interactions of Thiazole Abietane Inhibitors with the Human Serine Hydrolases ABHD16A and ABHD12. ACS Med Chem Lett 2023; 14:1404-1410. [PMID: 37849541 PMCID: PMC10577890 DOI: 10.1021/acsmedchemlett.3c00313] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 09/11/2023] [Indexed: 10/19/2023] Open
Abstract
12-Thiazole abietanes are highly selective reversible inhibitors of hABHD16A that could potentially alleviate neuroinflammation. In this study, we used synthetic chemistry, competitive activity-based protein profiling, and computational methodologies to try to establish relevant structural determinants of activity and selectivity of this class of compounds for inhibiting ABHD16A over ABHD12. Five compounds significantly inhibited hABHD16A but also very efficiently discriminated between inhibition of hABHD16A and hABHD12, with compound 35 being the most effective, at 100 μM (55.1 ± 8.7%; p < 0.0001). However, an outstanding switch in the selectivity toward ABHD12 was observed in the presence of a ring A ester, if the C2' position of the thiazole ring possessed a 1-hydroxyethyl group, as in compound 28. Although our data were inconclusive as to whether the observed enzyme inhibition is allosteric or not, we anticipate that the structure-activity relationships presented herein will inspire future drug discovery efforts in this field.
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Affiliation(s)
- Tiina
J. Ahonen
- Drug
Research Program, Division of Pharmaceutical Chemistry and Technology,
Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland
| | - Choa P. Ng
- Research
Centre for Health and Life Sciences, Coventry
University, CV1 5RW Coventry, U.K.
| | - Beatriz Farinha
- BioISI—Biosystems
& Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisboa, Portugal
| | - Bárbara Almeida
- BioISI—Biosystems
& Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisboa, Portugal
| | - Bruno L. Victor
- BioISI—Biosystems
& Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisboa, Portugal
| | - Christopher Reynolds
- Research
Centre for Health and Life Sciences, Coventry
University, CV1 5RW Coventry, U.K.
- School
of Life Sciences, University of Essex, CO4 3SQ Colchester, U.K.
| | - Eija Kalso
- Department
of Pharmacology, Faculty of Medicine, University
of Helsinki, 00014 Helsinki, Finland
- Department
of Anaesthesiology, Intensive Care and Pain Medicine, Helsinki University Hospital and University of Helsinki, FI-00029 Helsinki, Finland
| | - Jari Yli-Kauhaluoma
- Drug
Research Program, Division of Pharmaceutical Chemistry and Technology,
Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland
| | - Jennifer Greaves
- Research
Centre for Health and Life Sciences, Coventry
University, CV1 5RW Coventry, U.K.
| | - Vânia M. Moreira
- Drug
Research Program, Division of Pharmaceutical Chemistry and Technology,
Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland
- Centre
for Neuroscience and Cell Biology, and Centre for Innovative Biomedicine
and Biotechnology, University of Coimbra, 3000-548 Coimbra, Portugal
- Laboratory
of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
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18
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Islam MK, Khan M, Gidwani K, Witwer KW, Lamminmäki U, Leivo J. Lectins as potential tools for cancer biomarker discovery from extracellular vesicles. Biomark Res 2023; 11:85. [PMID: 37773167 PMCID: PMC10540341 DOI: 10.1186/s40364-023-00520-6] [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: 06/12/2023] [Accepted: 09/01/2023] [Indexed: 10/01/2023] Open
Abstract
Extracellular vesicles (EVs) have considerable potential as diagnostic, prognostic, and therapeutic agents, in large part because molecular patterns on the EV surface betray the cell of origin and may also be used to "target" EVs to specific cells. Cancer is associated with alterations to cellular and EV glycosylation patterns, and the surface of EVs is enriched with glycan moieties. Glycoconjugates of EVs play versatile roles in cancer including modulating immune response, affecting tumor cell behavior and site of metastasis and as such, paving the way for the development of innovative diagnostic tools and novel therapies. Entities that recognize specific glycans, such as lectins, may thus be powerful tools to discover and detect novel cancer biomarkers. Indeed, the past decade has seen a constant increase in the number of published articles on lectin-based strategies for the detection of EV glycans. This review explores the roles of EV glycosylation in cancer and cancer-related applications. Furthermore, this review summarizes the potential of lectins and lectin-based methods for screening, targeting, separation, and possible identification of improved biomarkers from the surface of EVs.
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Affiliation(s)
- Md Khirul Islam
- Department of Life Technologies, Division of Biotechnology, University of Turku, Kiinamyllynkatu 10, 20014, Turku, Finland.
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland.
| | - Misba Khan
- Department of Life Technologies, Division of Biotechnology, University of Turku, Kiinamyllynkatu 10, 20014, Turku, Finland
| | - Kamlesh Gidwani
- Department of Life Technologies, Division of Biotechnology, University of Turku, Kiinamyllynkatu 10, 20014, Turku, Finland
| | - Kenneth W Witwer
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Urpo Lamminmäki
- Department of Life Technologies, Division of Biotechnology, University of Turku, Kiinamyllynkatu 10, 20014, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Janne Leivo
- Department of Life Technologies, Division of Biotechnology, University of Turku, Kiinamyllynkatu 10, 20014, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
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19
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Zhou Q, Wang J, Zhang H, Sun L, Liu J, Meng L, Li J. Tumor-derived exosomes RNA expression profiling identifies the prognosis, immune characteristics, and treatment in HR+/HER2-breast cancer. Aging (Albany NY) 2023; 15:8471-8486. [PMID: 37647033 PMCID: PMC10497011 DOI: 10.18632/aging.204986] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 07/15/2023] [Indexed: 09/01/2023]
Abstract
Exosomes play crucial roles in intercellular communication and are involved in the onset and progression of various types of cancers, including breast cancer. However, the RNA composition of breast cancer-derived exosomes has not been comprehensively explored. We conducted microarray assays on exosomes isolated from breast cancer and healthy breast epithelial cells from three patients with hormone receptor (HR) +/ human epidermal growth factor receptor (HER2) - breast cancer and identified 817 differentially expressed genes (DEGs). Among these, 315 upregulated tumor-derived exosome genes (UTEGs) were used to classify HR+/HER2- breast cancers into two categories, revealing a difference in survival rates between the groups. We developed and validated a novel prognostic exosome score (ES) model consisting of four UTEGs that provides a refined prognosis prediction in HR+/HER2-breast cancer. ES reflects various immune-related features, including somatic variation, immunogenicity, and tumor immune infiltrate composition. Our findings indicate a considerable positive correlation between the ES and drug sensitivity values for vincristine, paclitaxel, and docetaxel. However, ES was remarkably higher in the endocrine therapy non-responder group than in the responder group. Immunohistochemistry confirmed the remarkable expression of the four model genes in tumor tissues, and their expression in MCF-7 cell exosomes was higher than that in MCF10A cells, as verified via qPCR. In summary, tumor-derived exosome genes provide novel insights into the subtyping, prognosis, and treatment of HR+/HER2-breast cancer.
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Affiliation(s)
- Qi Zhou
- Department of Breast Surgery, People’s Hospital of Tangshan, Tangshan 063001, Hebei, China
| | - Jing Wang
- Department of Breast Center, People’s Hospital of Tangshan, Tangshan 063001, Hebei, China
| | - Haiping Zhang
- Department of Breast Surgery, People’s Hospital of Tangshan, Tangshan 063001, Hebei, China
| | - Lu Sun
- Department of Oncology, Tangshan People’s Hospital, Tangshan 063001, Hebei, China
| | - Jingjing Liu
- Department of Oncology, Tangshan People’s Hospital, Tangshan 063001, Hebei, China
| | - Lingchao Meng
- Department of Pathology, Tangshan People’s Hospital, Tangshan 063001, Hebei, China
| | - Jingwu Li
- The Cancer Institute, Tangshan People’s Hospital, Tangshan 063001, Hebei, China
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20
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Wang Z, He M, He H, Kilby K, Antueno RD, Castle E, McMullen N, Qian Z, Zeev-Ben-Mordehai T, Duncan R, Pan C. Nonenveloped Avian Reoviruses Released with Small Extracellular Vesicles Are Highly Infectious. Viruses 2023; 15:1610. [PMID: 37515296 PMCID: PMC10384003 DOI: 10.3390/v15071610] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/20/2023] [Accepted: 07/21/2023] [Indexed: 07/30/2023] Open
Abstract
Vesicle-encapsulated nonenveloped viruses are a recently recognized alternate form of nonenveloped viruses that can avoid immune detection and potentially increase systemic transmission. Avian orthoreoviruses (ARVs) are the leading cause of various disease conditions among birds and poultry. However, whether ARVs use cellular vesicle trafficking routes for egress and cell-to-cell transmission is still poorly understood. We demonstrated that fusogenic ARV-infected quail cells generated small (~100 nm diameter) extracellular vesicles (EVs) that contained electron-dense material when observed by transmission electron microscope. Cryo-EM tomography indicated that these vesicles did not contain ARV virions or core particles, but the EV fractions of OptiPrep gradients did contain a small percent of the ARV virions released from cells. Western blotting of detergent-treated EVs revealed that soluble virus proteins and the fusogenic p10 FAST protein were contained within the EVs. Notably, virus particles mixed with the EVs were up to 50 times more infectious than virions alone. These results suggest that EVs and perhaps fusogenic FAST-EVs could contribute to ARV virulence.
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Affiliation(s)
- Zuopei Wang
- Laboratory of Molecular Virology and Immunology, Technology Innovation Center, Haid Research Institute, Guangdong Haid Group Co., Ltd., Panyu, Guangzhou 511400, China
| | - Menghan He
- Laboratory of Molecular Virology and Immunology, Technology Innovation Center, Haid Research Institute, Guangdong Haid Group Co., Ltd., Panyu, Guangzhou 511400, China
| | - Han He
- Department of Microbiology & Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Kyle Kilby
- Department of Microbiology & Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Roberto de Antueno
- Department of Microbiology & Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Elizabeth Castle
- Department of Microbiology & Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Nichole McMullen
- Department of Microbiology & Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Zhuoyu Qian
- Department of Biochemical Engineering, University College London, London WC1E 6BT, UK
| | | | - Roy Duncan
- Department of Microbiology & Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Chungen Pan
- Laboratory of Molecular Virology and Immunology, Technology Innovation Center, Haid Research Institute, Guangdong Haid Group Co., Ltd., Panyu, Guangzhou 511400, China
- Department of Microbiology & Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
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21
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Kim M, Son IT, Noh GT, Woo SY, Lee RA, Oh BY. Exosomes Derived from Colon Cancer Cells Promote Tumor Progression and Affect the Tumor Microenvironment. J Clin Med 2023; 12:3905. [PMID: 37373600 DOI: 10.3390/jcm12123905] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/01/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023] Open
Abstract
Cancer-cell-derived exosomes confer oncogenic properties in their tumor microenvironment and to other cells; however, the exact mechanism underlying this process is unclear. Here, we investigated the roles of cancer-cell-derived exosomes in colon cancer. Exosomes were isolated from colon cancer cell lines, HT-29, SW480, and LoVo, using an ExoQuick-TC kit, identified using Western blotting for exosome markers, and characterized using transmission electron microscopy and nanosight tracking analysis. The isolated exosomes were used to treat HT-29 to evaluate their effect on cancer progression, specifically cell viability and migration. Cancer-associated fibroblasts (CAFs) were obtained from patients with colorectal cancer to analyze the effect of the exosomes on the tumor microenvironment. RNA sequencing was performed to evaluate the effect of the exosomes on the mRNA component of CAFs. The results showed that exosome treatment significantly increased cancer cell proliferation, upregulated N-cadherin, and downregulated E-cadherin. Exosome-treated cells exhibited higher motility than control cells. Compared with control CAFs, exosome-treated CAFs showed more downregulated genes. The exosomes also altered the regulation of different genes involved in CAFs. In conclusion, colon cancer-cell-derived exosomes affect cancer cell proliferation and the epithelial-mesenchymal transition. They promote tumor progression and metastasis and affect the tumor microenvironment.
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Affiliation(s)
- Minsung Kim
- Department of Surgery, Hallym University College of Medicine, Anyang 14068, Republic of Korea
| | - Il Tae Son
- Department of Surgery, Hallym University College of Medicine, Anyang 14068, Republic of Korea
| | - Gyoung Tae Noh
- Department of Surgery, Ewha Womans University College of Medicine, Seoul 07804, Republic of Korea
| | - So-Youn Woo
- Department of Microbiology, Ewha Womans University College of Medicine, Seoul 03760, Republic of Korea
| | - Ryung-Ah Lee
- Department of Surgery, Ewha Womans University College of Medicine, Seoul 07804, Republic of Korea
| | - Bo Young Oh
- Department of Surgery, Hallym University College of Medicine, Anyang 14068, Republic of Korea
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22
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Van Dorpe S, Lippens L, Boiy R, Pinheiro C, Vergauwen G, Rappu P, Miinalainen I, Tummers P, Denys H, De Wever O, Hendrix A. Integrating automated liquid handling in the separation workflow of extracellular vesicles enhances specificity and reproducibility. J Nanobiotechnology 2023; 21:157. [PMID: 37208684 DOI: 10.1186/s12951-023-01917-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 04/28/2023] [Indexed: 05/21/2023] Open
Abstract
BACKGROUND Extracellular vesicles (EV) are extensively studied in human body fluids as potential biomarkers for numerous diseases. Major impediments of EV-based biomarker discovery include the specificity and reproducibility of EV sample preparation as well as intensive manual labor. We present an automated liquid handling workstation for the density-based separation of EV from human body fluids and compare its performance to manual handling by (in)experienced researchers. RESULTS Automated versus manual density-based separation of trackable recombinant extracellular vesicles (rEV) spiked in PBS significantly reduces variability in rEV recovery as quantified by fluorescent nanoparticle tracking analysis and ELISA. To validate automated density-based EV separation from complex body fluids, including blood plasma and urine, we assess reproducibility, recovery, and specificity by mass spectrometry-based proteomics and transmission electron microscopy. Method reproducibility is the highest in the automated procedure independent of the matrix used. While retaining (in urine) or enhancing (in plasma) EV recovery compared to manual liquid handling, automation significantly reduces the presence of body fluid specific abundant proteins in EV preparations, including apolipoproteins in plasma and Tamm-Horsfall protein in urine. CONCLUSIONS In conclusion, automated liquid handling ensures cost-effective EV separation from human body fluids with high reproducibility, specificity, and reduced hands-on time with the potential to enable larger-scale biomarker studies.
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Affiliation(s)
- Sofie Van Dorpe
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent, Belgium
- Department of Gynecology, Ghent University Hospital, Ghent, Belgium
| | - Lien Lippens
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent, Belgium
| | - Robin Boiy
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent, Belgium
| | - Cláudio Pinheiro
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent, Belgium
| | - Glenn Vergauwen
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent, Belgium
- Department of Gynecology, Ghent University Hospital, Ghent, Belgium
| | - Pekka Rappu
- Department of Life Technologies, University of Turku, Turku, Finland
| | | | - Philippe Tummers
- Cancer Research Institute Ghent, Ghent, Belgium
- Department of Gynecology, Ghent University Hospital, Ghent, Belgium
| | - Hannelore Denys
- Cancer Research Institute Ghent, Ghent, Belgium
- Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium
| | - Olivier De Wever
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent, Belgium
| | - An Hendrix
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Ghent University, Ghent, Belgium.
- Cancer Research Institute Ghent, Ghent, Belgium.
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23
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Vallejos PA, Gonda A, Yu J, Sullivan BG, Ostowari A, Kwong ML, Choi A, Selleck MJ, Kabagwira J, Fuller RN, Gironda DJ, Levine EA, Hughes CCW, Wall NR, Miller LD, Senthil M. Plasma Exosome Gene Signature Differentiates Colon Cancer from Healthy Controls. Ann Surg Oncol 2023; 30:3833-3844. [PMID: 36864326 PMCID: PMC10175396 DOI: 10.1245/s10434-023-13219-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 01/02/2023] [Indexed: 03/04/2023]
Abstract
BACKGROUND Liquid biopsies have become an integral part of cancer management as minimally invasive options to detect molecular and genetic changes. However, current options show poor sensitivity in peritoneal carcinomatosis (PC). Novel exosome-based liquid biopsies may provide critical information on these challenging tumors. In this initial feasibility analysis, we identified an exosome gene signature of 445 genes (ExoSig445) from colon cancer patients, including those with PC, that is distinct from healthy controls. METHODS Plasma exosomes from 42 patients with metastatic and non-metastatic colon cancer and 10 healthy controls were isolated and verified. RNAseq analysis of exosomal RNA was performed and differentially expressed genes (DEGs) were identified by the DESeq2 algorithm. The ability of RNA transcripts to discriminate control and cancer cases was assessed by principal component analysis (PCA) and Bayesian compound covariate predictor classification. An exosomal gene signature was compared with tumor expression profiles of The Cancer Genome Atlas. RESULTS Unsupervised PCA using exosomal genes with greatest expression variance showed stark separation between controls and patient samples. Using separate training and test sets, gene classifiers were constructed capable of discriminating control and patient samples with 100% accuracy. Using a stringent statistical threshold, 445 DEGs fully delineated control from cancer samples. Furthermore, 58 of these exosomal DEGs were found to be overexpressed in colon tumors. CONCLUSIONS Plasma exosomal RNAs can robustly discriminate colon cancer patients, including patients with PC, from healthy controls. ExoSig445 can potentially be developed as a highly sensitive liquid biopsy test in colon cancer.
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Affiliation(s)
- Paul A Vallejos
- Department of Basic Science, Division of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA.,Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Amber Gonda
- Department of Surgery, Division of Surgical Oncology, University of California, Irvine Medical Center, Orange, CA, USA
| | - Jingjing Yu
- Department of Surgery, Division of Surgical Oncology, University of California, Irvine Medical Center, Orange, CA, USA
| | - Brittany G Sullivan
- Department of Surgery, Division of Surgical Oncology, University of California, Irvine Medical Center, Orange, CA, USA
| | - Arsha Ostowari
- Department of Surgery, Division of Surgical Oncology, University of California, Irvine Medical Center, Orange, CA, USA
| | - Mei Li Kwong
- Division of Surgical Oncology, Loma Linda University Health, Loma Linda, CA, USA
| | - Audrey Choi
- Division of Surgical Oncology, Loma Linda University Health, Loma Linda, CA, USA
| | - Matthew J Selleck
- Division of Surgical Oncology, Loma Linda University Health, Loma Linda, CA, USA
| | - Janviere Kabagwira
- Department of Basic Science, Division of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA.,Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Ryan N Fuller
- Department of Basic Science, Division of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA.,Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Daniel J Gironda
- Department of Cancer Biology, Wake Forest Health, Winston-Salem, NC, USA
| | - Edward A Levine
- Department of Surgery, Division of Surgical Oncology, Wake Forest Health, Winston-Salem, NC, USA
| | - Christopher C W Hughes
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA
| | - Nathan R Wall
- Department of Basic Science, Division of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA.,Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Lance D Miller
- Department of Cancer Biology, Wake Forest Health, Winston-Salem, NC, USA
| | - Maheswari Senthil
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA.
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24
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Saadeldin IM, Ehab S, Swelum AA. Potential roles of extracellular vesicles as a noninvasive tool for prenatal genetic diagnosis. F&S SCIENCE 2023; 4:36-43. [PMID: 36736894 DOI: 10.1016/j.xfss.2023.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 01/03/2023] [Accepted: 01/24/2023] [Indexed: 02/04/2023]
Abstract
The rate of infertility is increasing owing to genetic and environmental factors. Consequently, assisted reproductive technology has been introduced as an alternative. Bearing in mind the global trend toward the transfer of only one embryo, there is an increasing trend for assessing embryo quality before transfer through prenatal genetic diagnosis (PGD) tests. This ensures that the best-quality embryos are implanted into the uterus. In the in vitro fertilization cycle, PGD is not only used for diseases or quality checks before embryo freezing but also for evaluating unfortunate risks, such as aneuploidy, signs of early abortions, and preterm birth. However, traditional preimplantation genetic testing and screening approaches are invasive and harm the health of both the mother and embryo, raising the risk of miscarriage. In the last decade, embryonic extracellular vesicles (EVs) have been investigated and have emerged as a promising diagnostic tool. In this mini-review, we address the use of EVs as a noninvasive biomarker in PGD to test for biological hazards within the embryo without invading its cells. We summarize the state-of-the-art in the use of the embryo's EV content, genomic DNA, messenger RNA, and microRNA in the spent culture medium and their relationship with embryo quality, successful implantation, and pregnancy.
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Affiliation(s)
- Islam M Saadeldin
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea; Research Institute of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea.
| | - Seif Ehab
- Biomedical Sciences Program, Zewail City of Science and Technology, University of Science and Technology, Giza, Egypt; Zoology Graduate Program, Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
| | - Ayman A Swelum
- Department of Animal Production, College of Food and Agriculture Sciences, King Saud University, Riyadh, Saudi Arabia; Department of Theriogenology, Faculty of Veterinary Medicine, Zagazig University, Egypt
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25
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Zhu Y, Li X. Advances of Wnt Signalling Pathway in Colorectal Cancer. Cells 2023; 12:cells12030447. [PMID: 36766788 PMCID: PMC9913588 DOI: 10.3390/cells12030447] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 01/25/2023] [Accepted: 01/28/2023] [Indexed: 01/31/2023] Open
Abstract
Colorectal cancer (CRC) represents one of the most common cancers worldwide, with a high mortality rate despite the decreasing incidence and new diagnostic and therapeutic strategies. CRC arises from both epidemiologic and molecular backgrounds. In addition to hereditary factor and genetic mutations, the strongly varying incidence of CRC is closely linked to chronic inflammatory disorders of the intestine and terrible dietary habits. The Wnt signalling pathway is a complex regulatory network that is implicated in many CRC physiological processes, including cancer occurrence, development, prognosis, invasion, and metastasis. It is currently believed to include classical Wnt/β-catenin, Wnt/PCP, and Wnt/Ca2+. In this review, we summarise the recent mechanisms and potential regulators of the three branches of the Wnt signalling pathway in CRC.
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Affiliation(s)
- Yaoyao Zhu
- Marine College, Shandong University, Weihai 264200, China
| | - Xia Li
- Marine College, Shandong University, Weihai 264200, China
- Shandong Kelun Pharmaceutical Co., Ltd., Binzhou 256600, China
- Correspondence: ; Tel.: +86-0531-8838-2612
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26
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Stefańska K, Józkowiak M, Angelova Volponi A, Shibli JA, Golkar-Narenji A, Antosik P, Bukowska D, Piotrowska-Kempisty H, Mozdziak P, Dzięgiel P, Podhorska-Okołów M, Zabel M, Dyszkiewicz-Konwińska M, Kempisty B. The Role of Exosomes in Human Carcinogenesis and Cancer Therapy-Recent Findings from Molecular and Clinical Research. Cells 2023; 12:cells12030356. [PMID: 36766698 PMCID: PMC9913699 DOI: 10.3390/cells12030356] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/06/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Exosomes are biological nanoscale spherical lipid bilayer vesicles, 40-160 nm in diameter, produced by most mammalian cells in both physiological and pathological conditions. Exosomes are formed via the endosomal sorting complex required for transport (ESCRT). The primary function of exosomes is mediating cell-to-cell communication. In terms of cancer, exosomes play important roles as mediators of intercellular communication, leading to tumor progression. Moreover, they can serve as biomarkers for cancer detection and progression. Therefore, their utilization in cancer therapies has been suggested, either as drug delivery carriers or as a diagnostic tool. However, exosomes were also reported to be involved in cancer drug resistance via transferring information of drug resistance to sensitive cells. It is important to consider the current knowledge regarding the role of exosomes in cancer, drug resistance, cancer therapies, and their clinical application in cancer therapies.
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Affiliation(s)
- Katarzyna Stefańska
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland
- Cellivia 3 S.A., 61-623 Poznan, Poland
| | - Małgorzata Józkowiak
- Department of Toxicology, Poznan University of Medical Sciences, 60-631 Poznan, Poland
| | - Ana Angelova Volponi
- Centre for Craniofacial and Regenerative Biology, Dental Institute, King’s College London, London WC2R 2LS, UK
| | - Jamil Awad Shibli
- Department of Periodontology and Oral Implantology, University of Guarulhos, Guarulhos 07030-010, Brazil
| | - Afsaneh Golkar-Narenji
- Prestage Department of Poultry Sciences, North Carolina State University, Raleigh, NC 27695, USA
| | - Paweł Antosik
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Dorota Bukowska
- Department of Diagnostics and Clinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Hanna Piotrowska-Kempisty
- Department of Toxicology, Poznan University of Medical Sciences, 60-631 Poznan, Poland
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Paul Mozdziak
- Prestage Department of Poultry Sciences, North Carolina State University, Raleigh, NC 27695, USA
| | - Piotr Dzięgiel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
| | - Marzenna Podhorska-Okołów
- Division of Ultrastructural Research, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
| | - Maciej Zabel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Division of Anatomy and Histology, University of Zielona Góra, 65-046 Zielona Góra, Poland
| | - Marta Dyszkiewicz-Konwińska
- Department of Biomaterials and Experimental Dentistry, Poznan University of Medical Sciences, 60-812 Poznan, Poland
| | - Bartosz Kempisty
- Prestage Department of Poultry Sciences, North Carolina State University, Raleigh, NC 27695, USA
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
- Division of Anatomy, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Department of Obstetrics and Gynecology, University Hospital and Masaryk University, 601 77 Brno, Czech Republic
- Correspondence:
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27
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Copy Number Variations as Determinants of Colorectal Tumor Progression in Liquid Biopsies. Int J Mol Sci 2023; 24:ijms24021738. [PMID: 36675253 PMCID: PMC9866722 DOI: 10.3390/ijms24021738] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/09/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
Over the years, increasing evidence has shown that copy number variations (CNVs) play an important role in the pathogenesis and prognosis of Colorectal Cancer (CRC). Colorectal adenomas are highly prevalent lesions, but only 5% of these adenomas ever progress to carcinoma. This review summarizes the different CNVs associated with adenoma-carcinoma CRC progression and with CRC staging. Characterization of CNVs in circulating free-RNA and in blood-derived exosomes augers well with the potential of using such assays for patient management and early detection of metastasis. To overcome the limitations related to tissue biopsies and tumor heterogeneity, using CNVs to characterize tumor-derived materials in biofluids provides less invasive sampling methods and a sample that collectively represents multiple tumor sites in heterogeneous samples. Liquid biopsies provide a source of circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), tumor-derived exosomes (TDE), circulating free RNA, and non-coding RNA. This review provides an overview of the current diagnostic and predictive models from liquid biopsies.
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28
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Heck KA, Lindholm HT, Niederdorfer B, Tsirvouli E, Kuiper M, Flobak Å, Lægreid A, Thommesen L. Characterisation of Colorectal Cancer Cell Lines through Proteomic Profiling of Their Extracellular Vesicles. Proteomes 2023; 11:proteomes11010003. [PMID: 36648961 PMCID: PMC9844407 DOI: 10.3390/proteomes11010003] [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: 10/24/2022] [Revised: 01/07/2023] [Accepted: 01/09/2023] [Indexed: 01/13/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent cancers, driven by several factors including deregulations in intracellular signalling pathways. Small extracellular vesicles (sEVs) are nanosized protein-packaged particles released from cells, which are present in liquid biopsies. Here, we characterised the proteome landscape of sEVs and their cells of origin in three CRC cell lines HCT116, HT29 and SW620 to explore molecular traits that could be exploited as cancer biomarker candidates and how intracellular signalling can be assessed by sEV analysis instead of directly obtaining the cell of origin itself. Our findings revealed that sEV cargo clearly reflects its cell of origin with proteins of the PI3K-AKT pathway highly represented in sEVs. Proteins known to be involved in CRC were detected in both cells and sEVs including KRAS, ARAF, mTOR, PDPK1 and MAPK1, while TGFB1 and TGFBR2, known to be key players in epithelial cancer carcinogenesis, were found to be enriched in sEVs. Furthermore, the phosphopeptide-enriched profiling of cell lysates demonstrated a distinct pattern between cell lines and highlighted potential phosphoproteomic targets to be investigated in sEVs. The total proteomic and phosphoproteomics profiles described in the current work can serve as a source to identify candidates for cancer biomarkers that can potentially be assessed from liquid biopsies.
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Affiliation(s)
- Kathleen A. Heck
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway
| | - Håvard T. Lindholm
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway
| | - Barbara Niederdorfer
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway
| | - Eirini Tsirvouli
- Department of Biology, Norwegian University of Science and Technology, 7491 Trondheim, Norway
| | - Martin Kuiper
- Department of Biology, Norwegian University of Science and Technology, 7491 Trondheim, Norway
| | - Åsmund Flobak
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway
- The Cancer Clinic, St. Olav’s University Hospital, 7030 Trondheim, Norway
| | - Astrid Lægreid
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway
| | - Liv Thommesen
- Department of Biomedical Laboratory Science, Norwegian University of Science and Technology, 7491 Trondheim, Norway
- Correspondence:
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29
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Lopez K, Lai SWT, Lopez Gonzalez EDJ, Dávila RG, Shuck SC. Extracellular vesicles: A dive into their role in the tumor microenvironment and cancer progression. Front Cell Dev Biol 2023; 11:1154576. [PMID: 37025182 PMCID: PMC10071009 DOI: 10.3389/fcell.2023.1154576] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 03/10/2023] [Indexed: 04/08/2023] Open
Abstract
Extracellular vesicles (EVs) encompass a diverse set of membrane-derived particles released from cells and are found in numerous biological matrices and the extracellular space. Specific classes of EVs include apoptotic bodies, exosomes, and microvesicles, which vary in their size, origin, membrane protein expression, and interior cargo. EVs provide a mechanism for shuttling cargo between cells, which can influence cell physiology by transporting proteins, DNA, and RNA. EVs are an abundant component of the tumor microenvironment (TME) and are proposed to drive tumor growth and progression by communicating between fibroblasts, macrophages, and tumor cells in the TME. The cargo, source, and type of EV influences the pro- or anti-tumoral role of these molecules. Therefore, robust EV isolation and characterization techniques are required to ensure accurate elucidation of their association with disease. Here, we summarize different EV subclasses, methods for EV isolation and characterization, and a selection of current clinical trials studying EVs. We also review key studies exploring the role and impact of EVs in the TME, including how EVs mediate intercellular communication, drive cancer progression, and remodel the TME.
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30
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Hirata T, Harada Y, Hirosawa KM, Tokoro Y, Suzuki KG, Kizuka Y. N-acetylglucosaminyltransferase-V (GnT-V)-enriched small extracellular vesicles mediate N-glycan remodeling in recipient cells. iScience 2022; 26:105747. [PMID: 36590176 PMCID: PMC9794981 DOI: 10.1016/j.isci.2022.105747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 11/09/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022] Open
Abstract
Small extracellular vesicles (sEVs) secreted from cancer cells play pivotal roles in cancer metastasis and malignancy by transferring biomolecules and conditioning future metastatic sites. Studies have elucidated structures and functions of glycans on sEVs; however, whether sEVs remodel glycans in recipient cells remains poorly understood. Here, we examined the enzyme activity of glycosyltransferases for complex N-glycan biosynthesis in cancer-derived sEVs and discovered that cancer-related glycosyltransferase, N-acetylglucosaminyltransferase-V (GnT-V, a.k.a. MGAT5), is selectively enriched in sEVs among various glycosyltransferases. GnT-V in sEVs is a cleaved form, and cleavage by SPPL3 protease is necessary for loading GnT-V in sEVs. Fractionation experiments and single-particle imaging further revealed that GnT-V was enriched in non-exosomal sEVs. Strikingly, we found that enzymatically active GnT-V in sEVs was transferred to recipient cells and the N-glycan structures of recipient cells were remodeled to express GnT-V-produced glycans. Our results suggest GnT-V-enriched sEVs' role in glycan remodeling in cancer metastasis.
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Affiliation(s)
- Tetsuya Hirata
- Laboratory of Glyco-biochemistry, Institute for Glyco-core Research (iGCORE), Gifu University, Gifu 501-1193, Japan
| | - Yoichiro Harada
- Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, Osaka 541-8567, Japan
| | - Koichiro M. Hirosawa
- Laboratory of Cell Biophysics, Institute for Glyco-core Research (iGCORE), Gifu University, Gifu 501-1193, Japan
| | - Yuko Tokoro
- Laboratory of Glyco-biochemistry, Institute for Glyco-core Research (iGCORE), Gifu University, Gifu 501-1193, Japan
| | - Kenichi G.N. Suzuki
- Laboratory of Cell Biophysics, Institute for Glyco-core Research (iGCORE), Gifu University, Gifu 501-1193, Japan
| | - Yasuhiko Kizuka
- Laboratory of Glyco-biochemistry, Institute for Glyco-core Research (iGCORE), Gifu University, Gifu 501-1193, Japan,Corresponding author
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31
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Adnani L, Spinelli C, Tawil N, Rak J. Role of extracellular vesicles in cancer-specific interactions between tumour cells and the vasculature. Semin Cancer Biol 2022; 87:196-213. [PMID: 36371024 DOI: 10.1016/j.semcancer.2022.11.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 09/25/2022] [Accepted: 11/08/2022] [Indexed: 11/11/2022]
Abstract
Cancer progression impacts and exploits the vascular system in several highly consequential ways. Among different types of vascular cells, blood cells and mediators that are engaged in these processes, endothelial cells are at the centre of the underlying circuitry, as crucial constituents of angiogenesis, angiocrine stimulation, non-angiogenic vascular growth, interactions with the coagulation system and other responses. Tumour-vascular interactions involve soluble factors, extracellular matrix molecules, cell-cell contacts, as well as extracellular vesicles (EVs) carrying assemblies of molecular effectors. Oncogenic mutations and transforming changes in the cancer cell genome, epigenome and signalling circuitry exert important and often cancer-specific influences upon pathways of tumour-vascular interactions, including the biogenesis, content, and biological activity of EVs and responses of cancer cells to them. Notably, EVs may carry and transfer bioactive, oncogenic macromolecules (oncoproteins, RNA, DNA) between tumour and vascular cells and thereby elicit unique functional changes and forms of vascular growth and remodeling. Cancer EVs influence the state of the vasculature both locally and systemically, as exemplified by cancer-associated thrombosis. EV-mediated communication pathways represent attractive targets for therapies aiming at modulation of the tumour-vascular interface (beyond angiogenesis) and could also be exploited for diagnostic purposes in cancer.
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Affiliation(s)
- Lata Adnani
- McGill University and Research Institute of the McGill University Health Centre, Canada
| | - Cristiana Spinelli
- McGill University and Research Institute of the McGill University Health Centre, Canada
| | - Nadim Tawil
- McGill University and Research Institute of the McGill University Health Centre, Canada
| | - Janusz Rak
- McGill University and Research Institute of the McGill University Health Centre, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada.
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32
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Joseph J, Rahmani B, Cole Y, Puttagunta N, Lin E, Khan ZK, Jain P. Can Soluble Immune Checkpoint Molecules on Exosomes Mediate Inflammation? J Neuroimmune Pharmacol 2022; 17:381-397. [PMID: 34697721 PMCID: PMC10128092 DOI: 10.1007/s11481-021-10018-3] [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: 05/04/2021] [Accepted: 08/25/2021] [Indexed: 01/13/2023]
Abstract
Immune checkpoints (ICPs) are major co-signaling pathways that trigger effector functions in immune cells, with isoforms that are either membrane bound, engaging in direct cell to cell activation locally, or soluble, acting at distant sites by circulating freely or potentially via extracellular vesicles (EVs). Exosomes are small EVs secreted by a variety of cells carrying various proteins and nucleic acids. They are distributed extensively through biological fluids and have major impacts on infectious diseases, cancer, and neuroinflammation. Similarly, ICPs play key roles in a variety of disease conditions and have been extensively utilized as a prognostic tool for various cancers. Herein, we explored if the association between exosomes and ICPs could be a significant contributor of inflammation, particularly in the setting of cancer, neuroinflammation and viral infections, wherein the up regulation in both exosomal proteins and ICPs correlate with immunosuppressive effects. The detailed literature review of existing data highlights the significance and complexity of these two important pathways in mediating cancer and potentiating neuroinflammation via modulating overall immune response. Cells increasingly secret exosomes in response to intracellular signals from invading pathogens or cancerous transformations. These exosomes can carry a variety of cargo including proteins, nucleic acids, cytokines, and receptors/ligands that have functional consequences on recipient cells. Illustration generated using BioRender software.
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Affiliation(s)
- Julie Joseph
- Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA, 19129, USA
| | - Benjamin Rahmani
- Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA, 19129, USA
| | - Yonesha Cole
- Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA, 19129, USA
| | - Neha Puttagunta
- Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA, 19129, USA
| | - Edward Lin
- Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA, 19129, USA
| | - Zafar K Khan
- Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA, 19129, USA
| | - Pooja Jain
- Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA, 19129, USA. .,Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA, 19129, USA.
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33
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Tenchov R, Sasso JM, Wang X, Liaw WS, Chen CA, Zhou QA. Exosomes─Nature's Lipid Nanoparticles, a Rising Star in Drug Delivery and Diagnostics. ACS NANO 2022; 16:17802-17846. [PMID: 36354238 PMCID: PMC9706680 DOI: 10.1021/acsnano.2c08774] [Citation(s) in RCA: 262] [Impact Index Per Article: 87.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 10/21/2022] [Indexed: 05/03/2023]
Abstract
Exosomes are a subgroup of nanosized extracellular vesicles enclosed by a lipid bilayer membrane and secreted by most eukaryotic cells. They represent a route of intercellular communication and participate in a wide variety of physiological and pathological processes. The biological roles of exosomes rely on their bioactive cargos, including proteins, nucleic acids, and lipids, which are delivered to target cells. Their distinctive properties─innate stability, low immunogenicity, biocompatibility, and good biomembrane penetration capacity─allow them to function as superior natural nanocarriers for efficient drug delivery. Another notably favorable clinical application of exosomes is in diagnostics. They hold various biomolecules from host cells, which are indicative of pathophysiological conditions; therefore, they are considered vital for biomarker discovery in clinical diagnostics. Here, we use data from the CAS Content Collection and provide a landscape overview of the current state and delineate trends in research advancement on exosome applications in therapeutics and diagnostics across time, geography, composition, cargo loading, and development pipelines. We discuss exosome composition and pathway, from their biogenesis and secretion from host cells to recipient cell uptake. We assess methods for exosome isolation and purification, their clinical applications in therapy and diagnostics, their development pipelines, the exploration goals of the companies, the assortment of diseases they aim to treat, development stages of their research, and publication trends. We hope this review will be useful for understanding the current knowledge in the field of medical applications of exosomes, in an effort to further solve the remaining challenges in fulfilling their potential.
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Affiliation(s)
- Rumiana Tenchov
- CAS, a Division of the American Chemical
Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United
States
| | - Janet M. Sasso
- CAS, a Division of the American Chemical
Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United
States
| | - Xinmei Wang
- CAS, a Division of the American Chemical
Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United
States
| | - Wen-Shing Liaw
- CAS, a Division of the American Chemical
Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United
States
| | - Chun-An Chen
- CAS, a Division of the American Chemical
Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United
States
| | - Qiongqiong Angela Zhou
- CAS, a Division of the American Chemical
Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United
States
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Nanostructured Silicon Enabled HR-MS for the Label-Free Detection of Biomarkers in Colorectal Cancer Plasma Small Extracellular Vesicles. JOURNAL OF NANOTHERANOSTICS 2022. [DOI: 10.3390/jnt3040013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Despite improvements in treatment options for advanced colorectal cancer (CRC), survival outcomes are still best for patients with non-metastasised disease. Diagnostic tools to identify blood-based biomarkers and assist in CRC subtype classification could afford a means to track CRC progression and treatment response. Cancer cell-derived small extracellular vesicles (EVs) circulating in blood carry an elevated cargo of lipids and proteins that could be used as a signature of tumour suppressor/promoting events or stages leading up to and including metastasis. Here, we used pre-characterised biobanked plasma samples from surgical units, typically with a low volume (~100 µL), to generate and discover signatures of CRC-derived EVs. We employed nanostructured porous silicon (pSi) surface assisted-laser desorption/ionisation (SALDI) coupled with high-resolution mass spectrometry (HR-MS), to allow sensitive detection of low abundant analytes in plasma EVs. When applied to CRC samples, SALDI-HR-MS enabled the detection of the peptide mass fingerprint of cancer suppressor proteins, including serine/threonine phosphatases and activating-transcription factor 3. SALDI-HR-MS also allowed the detection of a spectrum of glycerophospholipids and sphingolipid signatures in metastatic CRC. We observed that lithium chloride enhanced detection sensitivity to elucidate the structure of low abundant lipids in plasma EVs. pSi SALDI can be used as an effective system for label-free and high throughput analysis of low-volume patient samples, allowing rapid and sensitive analysis for CRC classification.
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35
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Kugeratski FG, Santi A, Zanivan S. Extracellular vesicles as central regulators of blood vessel function in cancer. Sci Signal 2022; 15:eaaz4742. [PMID: 36166511 DOI: 10.1126/scisignal.aaz4742] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Blood vessels deliver oxygen and nutrients that sustain tumor growth and enable the dissemination of cancer cells to distant sites and the recruitment of intratumoral immune cells. In addition, the structural and functional abnormalities of the tumor vasculature foster the development of an aggressive tumor microenvironment and impair the efficacy of existing cancer therapies. Extracellular vesicles (EVs) have emerged as major players of tumor progression, and a growing body of evidence has demonstrated that EVs derived from cancer cells trigger multiple responses in endothelial cells that alter blood vessel function in tumors. EV-mediated signaling in endothelial cells can occur through the transfer of functional cargos such as miRNAs, lncRNAs, cirRNAs, and proteins. Moreover, membrane-bound proteins in EVs can elicit receptor-mediated signaling in endothelial cells. Together, these mechanisms reprogram endothelial cells and contribute to the sustained exacerbated angiogenic signaling typical of tumors, which, in turn, influences cancer progression. Targeting these angiogenesis-promoting EV-dependent mechanisms may offer additional strategies to normalize tumor vasculature. Here, we discuss the current knowledge pertaining to the contribution of cancer cell-derived EVs in mechanisms regulating blood vessel functions in tumors. Moreover, we discuss the translational opportunities in targeting the dysfunctional tumor vasculature using EVs and highlight the open questions in the field of EV biology that can be addressed using mass spectrometry-based proteomics analysis.
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Affiliation(s)
- Fernanda G Kugeratski
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Alice Santi
- Department of Experimental and Clinical Biomedical Sciences, Università degli Studi di Firenze, 50134 Firenze, Italy
| | - Sara Zanivan
- CRUK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK
- School of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1QH, UK
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36
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Ozkocak DC, Phan TK, Poon IKH. Translating extracellular vesicle packaging into therapeutic applications. Front Immunol 2022; 13:946422. [PMID: 36045692 PMCID: PMC9420853 DOI: 10.3389/fimmu.2022.946422] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 07/18/2022] [Indexed: 11/23/2022] Open
Abstract
Extracellular vesicles (EVs) are membrane-bound particles released by cells in various (patho)physiological conditions. EVs can transfer effector molecules and elicit potent responses in recipient cells, making them attractive therapeutic agents and drug delivery platforms. In contrast to their tremendous potential, only a few EV-based therapies and drug delivery have been approved for clinical use, which is largely attributed to limited therapeutic loading technologies and efficiency. As EV cargo has major influence on their functionality, understanding and translating the biology underlying the packaging and transferring of biomolecule cargos (e.g. miRNAs, pathogen antigens, small molecule drugs) into EVs is key in harnessing their therapeutic potential. In this review, through recent insights into EVs’ content packaging, we discuss different mechanisms utilized by EVs during cargo packaging, and how one might therapeutically exploit this process. Apart from the well-characterized EVs like exosomes and microvesicles, we also cover the less-studied and other EV subtypes like apoptotic bodies, large oncosomes, bacterial outer membrane vesicles, and migrasomes to highlight therapeutically-diverse opportunities of EV armoury.
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37
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Šrajer Gajdošik M, Kovač Peić A, Begić M, Grbčić P, Brilliant KE, Hixson DC, Josić D. Possible Role of Extracellular Vesicles in Hepatotoxicity of Acetaminophen. Int J Mol Sci 2022; 23:8870. [PMID: 36012131 PMCID: PMC9408656 DOI: 10.3390/ijms23168870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 07/29/2022] [Accepted: 08/05/2022] [Indexed: 11/16/2022] Open
Abstract
We examined proteomic profiles of rat liver extracellular vesicles (EVs) shed following treatment with a sub-toxic dose (500 mg/kg) of the pain reliever drug, acetaminophen (APAP). EVs representing the entire complement of hepatic cells were isolated after perfusion of the intact liver and analyzed with LC-MS/MS. The investigation was focused on revealing the function and cellular origin of identified EVs proteins shed by different parenchymal and non-parenchymal liver cells and their possible role in an early response of this organ to a toxic environment. Comparison of EV proteomic profiles from control and APAP-treated animals revealed significant differences. Alpha-1-macroglobulin and members of the cytochrome P450 superfamily were highly abundant proteins in EVs shed by the normal liver. In contrast, proteins like aminopeptidase N, metalloreductase STEAP4, different surface antigens like CD14 and CD45, and most members of the annexin family were detected only in EVs that were shed by livers of APAP-treated animals. In EVs from treated livers, there was almost a complete disappearance of members of the cytochrome P450 superfamily and a major decrease in other enzymes involved in the detoxification of xenobiotics. Additionally, there were proteins that predominated in non-parenchymal liver cells and in the extracellular matrix, like fibronectin, receptor-type tyrosine-protein phosphatase C, and endothelial type gp91. These differences indicate that even treatment with a sub-toxic concentration of APAP initiates dramatic perturbation in the function of this vital organ.
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Affiliation(s)
| | | | - Marija Begić
- Faculty of Medicine, University Juraj Dobrila of Pula, 52100 Pula, Croatia
| | - Petra Grbčić
- Faculty of Medicine, University Juraj Dobrila of Pula, 52100 Pula, Croatia
| | - Kate E. Brilliant
- Proteomics Core, COBRE CCRD, Rhode Island Hospital, Providence, RI 02903, USA
- Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Douglas C. Hixson
- Proteomics Core, COBRE CCRD, Rhode Island Hospital, Providence, RI 02903, USA
- Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Djuro Josić
- Faculty of Medicine, University Juraj Dobrila of Pula, 52100 Pula, Croatia
- Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
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38
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Fu Z, Yuan Y. The role of tumor neogenesis pipelines in tumor progression and their therapeutic potential. Cancer Med 2022; 12:1558-1571. [PMID: 35832030 PMCID: PMC9883577 DOI: 10.1002/cam4.4979] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 05/27/2022] [Accepted: 06/11/2022] [Indexed: 02/02/2023] Open
Abstract
Pipeline formation between tumor cells and the tumor microenvironment (TME) is a key event leading to tumor progression. These pipelines include blood vessels, lymphatics, and membranous vessels (the former two can be collectively referred to as vasculature). Pipeline regeneration is a feature of all solid tumors; it delivers nutrients to tumors and promotes tumor invasion and metastasis such that cancer cells grow rapidly, escape unfavorable TME, spread to secondary sites, generate tumor drug resistance, and promote postoperative tumor recurrence. Novel tumor therapy strategies must exploit the molecular mechanisms underpinning these pipelines to facilitate more targeted drug therapies. In this review, pipeline generation, influencing factors, pipeline functions during tumor progression, and pipeline potential as drug targets are systematically summarized.
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Affiliation(s)
- Zhanqi Fu
- Tumor Etiology and Screening Department of Cancer Institute and General SurgeryThe First Hospital of China Medical UniversityShenyangChina,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education DepartmentThe First Hospital of China Medical UniversityShenyangChina,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning ProvinceThe First Hospital of China Medical UniversityShenyangChina
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General SurgeryThe First Hospital of China Medical UniversityShenyangChina,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education DepartmentThe First Hospital of China Medical UniversityShenyangChina,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning ProvinceThe First Hospital of China Medical UniversityShenyangChina
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39
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Pandian SRK, Vijayakumar KK, Kunjiappan S, Babkiewicz E, Maszczyk P. Emerging role of exosomes in hematological malignancies. Clin Exp Med 2022:10.1007/s10238-022-00850-z. [PMID: 35798882 DOI: 10.1007/s10238-022-00850-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 06/09/2022] [Indexed: 02/08/2023]
Abstract
Hematological malignancies are a heterogeneous group of neoplasms in the blood characterized by dysregulated hematopoiesis and classified as leukemia, lymphoma, and myeloma. The occurrence and progression of hematological malignancies depend on transformed hematopoietic stem cells, which refract to chemotherapy and often cause relapse. In recent years, monoclonal antibody therapies are preferred for hematopoietic cancers, owing to their inherent mechanisms of action and improved outcomes. However, efficient drug delivery methods and the establishment of novel biomarkers are currently being investigated and warranted to improve the outcome of patients with hematological malignancies. For instance, non-viral-mediated, natural carriers have been suggested for latent intracellular drug delivery. In this purview, repurposing small vesicles (e.g., exosomes) is considered a latent approach for myeloma therapy. Exosomes (nano-vesicles) have many advantages in that they are secreted by various animals and plants and become sought after for therapeutic and diagnostic purposes. The size of the cellular membrane of exosomes (30-150 nm) facilitates ligand binding and targeted delivery of the loaded molecules. Furthermore, exosomes can be modified to express specific target moiety on their cell membrane and can also be featured with desired biological activity, thereby potentially employed for various convoluted diseases, including hematological malignancies. To advance the current knowledge, this review is focused on the source, composition, function and surface engineering of exosomes pertaining to hematological malignancies.
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Affiliation(s)
- Sureshbabu Ram Kumar Pandian
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil, Tamil Nadu, 626126, India.
| | - Kevin Kumar Vijayakumar
- School of Biotechnology, Department of Molecular Microbiology, Madurai Kamaraj University, Palkalai Nagar, Madurai, Tamil Nadu, 625021, India
| | - Selvaraj Kunjiappan
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil, Tamil Nadu, 626126, India
| | - Ewa Babkiewicz
- Department of Hydrobiology, Faculty of Biology, University of Warsaw at Biology & Chemistry Research Center, 02-089, Warsaw, Poland
| | - Piotr Maszczyk
- Department of Hydrobiology, Faculty of Biology, University of Warsaw at Biology & Chemistry Research Center, 02-089, Warsaw, Poland
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40
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Yu B, Zhou S, Long D, Ning Y, Yao H, Zhou E, Wang Y. DDX55 promotes HCC progression via interacting with BRD4 and participating in exosome-mediated cell-cell communication. Cancer Sci 2022; 113:3002-3017. [PMID: 35514200 PMCID: PMC9459289 DOI: 10.1111/cas.15393] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 04/26/2022] [Accepted: 04/30/2022] [Indexed: 11/27/2022] Open
Abstract
The involvement of DEAD‐box helicase 55 (DDX55) in oncogenesis has been suggested, but its biological role in hepatocellular carcinoma (HCC) remains unknown. The present study verified the upregulation of DDX55 in HCC tissues compared with non‐tumor controls. DDX55 displayed the highest prognostic values among the DEAD‐box protein family for recurrence‐free survival and overall survival of HCC patients. In addition, the effects of DDX55 in the promotion of HCC cell proliferation, migration, and invasion were determined ex vivo and in vivo. Mechanistically, we revealed that DDX55 could interact with BRD4 to form a transcriptional regulatory complex that positively regulated PIK3CA transcription. Following that, β‐catenin signaling was activated in a PI3K/Akt/GSK‐3β dependent manner, thus inducing cell cycle progression and epithelial–mesenchymal transition. Intriguingly, both DDX55 mRNA and protein were identified in the exosomes derived from HCC cells. Exosomal DDX55 was implicated in intercellular communication between HCC cells with high or low DDX55 levels and between HCC cells and endothelial cells, thereby promoting the malignant phenotype of HCC cells and angiogenesis. In conclusion, DDX55 may be a valuable prognostic biomarker and therapeutic target in HCC.
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Affiliation(s)
- Bin Yu
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Engineering Center of Natural Polymer-based Medical Materials, Hubei, Wuhan, China
| | - Shujun Zhou
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Engineering Center of Natural Polymer-based Medical Materials, Hubei, Wuhan, China
| | - Dakun Long
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Engineering Center of Natural Polymer-based Medical Materials, Hubei, Wuhan, China
| | - Yuxiang Ning
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Engineering Center of Natural Polymer-based Medical Materials, Hubei, Wuhan, China
| | - Hanlin Yao
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Engineering Center of Natural Polymer-based Medical Materials, Hubei, Wuhan, China
| | - Encheng Zhou
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Engineering Center of Natural Polymer-based Medical Materials, Hubei, Wuhan, China
| | - Yanfeng Wang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Engineering Center of Natural Polymer-based Medical Materials, Hubei, Wuhan, China
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41
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LncRNA Biomarkers of Inflammation and Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1363:121-145. [PMID: 35220568 DOI: 10.1007/978-3-030-92034-0_7] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Long noncoding RNAs (lncRNAs) are promising candidates as biomarkers of inflammation and cancer. LncRNAs have several properties that make them well-suited as molecular markers of disease: (1) many lncRNAs are expressed in a tissue-specific manner, (2) distinct lncRNAs are upregulated based on different inflammatory or oncogenic stimuli, (3) lncRNAs released from cells are packaged and protected in extracellular vesicles, and (4) circulating lncRNAs in the blood are detectable using various RNA sequencing approaches. Here we focus on the potential for lncRNA biomarkers to detect inflammation and cancer, highlighting key biological, technological, and analytical considerations that will help advance the development of lncRNA-based liquid biopsies.
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42
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Bhat A, Yadav J, Thakur K, Aggarwal N, Chhokar A, Tripathi T, Singh T, Jadli M, Veerapandian V, Bharti AC. Transcriptome analysis of cervical cancer exosomes and detection of HPVE6*I transcripts in exosomal RNA. BMC Cancer 2022; 22:164. [PMID: 35148692 PMCID: PMC8840784 DOI: 10.1186/s12885-022-09262-4] [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: 09/06/2021] [Accepted: 01/25/2022] [Indexed: 12/21/2022] Open
Abstract
Background Exosomes play a key role in cell-to-cell communication and are integral component of the tumor microenvironment. Recent observations suggest transfer of RNA through tumor-derived exosomes that can potentially translate into regulatory proteins in the recipient cells. Role of cervical cancer-derived exosomes and their transcript cargo is poorly understood. Materials and methods The total RNA of exosomes from HPV-positive (SiHa and HeLa) and HPV-negative (C33a) cervical cancer cell lines were extracted and the transcripts were estimated using Illumina HiSeq X. Further, validation of HPV transcripts were performed using RT-PCR. Results 3099 transcripts were found to be differentially-exported in HPV-positive vs. HPV-negative exosomes (p value <0.05). Analysis of top 10 GO terms and KEGG pathways showed enrichment of transcripts belonging to axon guidance and tumor innervation in HPV-positive exosomes. Among top 20 overexpressed transcripts, EVC2, LUZP1 and ANKS1B were the most notable due to their involvement in Hh signaling, cellular migration and invasion, respectively. Further, low levels of HPV-specific reads were detected. RT-PCR validation revealed presence of E6*I splice variant of HPV18 in exosomal RNA of HeLa cells. The E6*I transcripts were consistently retained in exosomes obtained from HeLa cells undergoing 5-FU and cisplatin-induced oxidative stress. Conclusion Our data suggests the enrichment of poly-A RNA transcripts in the exosomal cargo of cervical cancer cells, which includes pro-tumorigenic cellular RNA and viral transcripts such as HPV E6, which may have clinical utility as potential exosomal biomarkers of cervical cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09262-4.
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Affiliation(s)
- Anjali Bhat
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | - Joni Yadav
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | - Kulbhushan Thakur
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | - Nikita Aggarwal
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | - Arun Chhokar
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | - Tanya Tripathi
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | - Tejveer Singh
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | - Mohit Jadli
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | | | - Alok Chandra Bharti
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India.
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43
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Rana R, Kant R, Kaul D, Sachdev A, Ganguly NK. Integrated view of molecular diagnosis and prognosis of dengue viral infection: future prospect of exosomes biomarkers. Mol Cell Biochem 2022; 477:815-832. [PMID: 35059925 DOI: 10.1007/s11010-021-04326-8] [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: 07/16/2021] [Accepted: 12/03/2021] [Indexed: 10/19/2022]
Abstract
Dengue viruses (DENVs) are the viruses responsible for dengue infection which affects lungs, liver, heart and also other organs of individuals. DENVs consist of the group of four serotypically diverse dengue viruses transmitted in tropical and sub-tropical countries of world. Aedes mosquito is the principal vector which spread the infection from infected person to healthy humans. DENVs can cause different syndromes depending on serotype of virus which range from undifferentiated mild fever to dengue hemorrhagic fever resulting in vascular leakage due to release of cytokine and Dengue shock syndrome with fluid loss and hypotensive shock, or other severe manifestations such as bleeding and organ failure. Increase in dengue cases in pediatric population is a major concern. Transmission of dengue depends on various factors like temperature, rainfall, and distribution of Aedes aegypti mosquitoes. The present review describes a comprehensive overview of dengue, pathophysiology, diagnosis, treatment with an emphasis on potential of exosomes as biomarkers for early prediction of dengue in pediatrics.
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Affiliation(s)
- Rashmi Rana
- Department of Research, Sir Ganga Ram Hospital, New Delhi, 110060, India.
| | - Ravi Kant
- Department of Research, Sir Ganga Ram Hospital, New Delhi, 110060, India
| | - Dinesh Kaul
- Department of Pediatrics, Sir Ganga Ram Hospital, New Delhi, 110060, India
| | - Anil Sachdev
- Department of Pediatrics, Sir Ganga Ram Hospital, New Delhi, 110060, India
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Khan MA, Anand S, Deshmukh SK, Singh S, Singh AP. Determining the Size Distribution and Integrity of Extracellular Vesicles by Dynamic Light Scattering. Methods Mol Biol 2022; 2413:165-175. [PMID: 35044664 PMCID: PMC10942725 DOI: 10.1007/978-1-0716-1896-7_17] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Extracellular vesicles (EVs) have emerged as significant players in intercellular communication. They carry crucial biological information, and their uptake induces changes in the biological functioning and phenotypes of the recipient cell. Thus, there has been a great deal of interest in understanding their roles in the pathobiology of benign diseases and cancer. Moreover, EVs carry the molecular signatures of the donor cells, and therefore, their utility in biomarker development is being explored. Investigations are also underway to exploit their natural property of cargo transfer from one cell to another to develop efficient, nontoxic, and nonimmunogenic drug delivery systems. EVs originate through endosomal pathways, membrane-budding, or membrane-blebbing during apoptosis. These EV subtypes are usually expected to follow a specific size and surface marker distribution reflective of their origin; however, variations are often reported, especially under pathobiological conditions. Therefore, they are categorized mainly based on their size distribution as small, medium, and large EVs. Dynamic Light Scattering (DLS) is frequently used to measure the size distribution of nanoscale particles in a solution. Moreover, it also provides data on other biophysical properties such as polydispersity, aggregation, solubility, viscosity, and stability. This chapter describes the methods for determining the size distribution and integrity of EVs using DLS along with some constraints associated with the practical use of the technology.
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Affiliation(s)
- Mohammad Aslam Khan
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA
- Cancer Biology Program, Mitchell Cancer Institute, Mobile, AL, USA
| | - Shashi Anand
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA
- Cancer Biology Program, Mitchell Cancer Institute, Mobile, AL, USA
| | - Sachin Kumar Deshmukh
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA
- Cancer Biology Program, Mitchell Cancer Institute, Mobile, AL, USA
| | - Seema Singh
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA
- Cancer Biology Program, Mitchell Cancer Institute, Mobile, AL, USA
- Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, USA
| | - Ajay Pratap Singh
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA.
- Cancer Biology Program, Mitchell Cancer Institute, Mobile, AL, USA.
- Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, USA.
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45
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Dang Y, Zhang S, Wang Y, Zhao G, Chen C, Jiang W. State-of-the-Art: Exosomes in Colorectal Cancer. Curr Cancer Drug Targets 2021; 22:2-17. [PMID: 34758717 DOI: 10.2174/1568009621666211110094442] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 08/06/2021] [Accepted: 09/09/2021] [Indexed: 11/22/2022]
Abstract
Colorectal cancer (CRC) has a high prevalence and mortality rate, globally. To date, the progression mechanisms of CRC are still elusive. Exosomes (~100 nm in diameter) correspond to a subset of extracellular vesicles formed by an array of cancerous cells and stromal cells. These particular nanovesicles carry and transmit bioactive molecules, like proteins, lipids, and genetic materials, which mediate the crosstalk between cancer cells and the microenvironment. Accumulating evidence has shown the decisive functions of exosomes in the development, metastasis, and therapy resistance of CRC. Furthermore, some recent studies have also revealed the abilities of exosomes to function as either biomarkers or therapeutic targets for CRC. This review focuses on the specific mechanisms of exosomes in regulating CRC progression, and summarizes the potential clinical applications of exosomes in the diagnosis and therapy of CRC.
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Affiliation(s)
- Yan Dang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing. China
| | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing. China
| | - Yongjun Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing. China
| | - Guiping Zhao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing. China
| | - Chuyan Chen
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing. China
| | - Wei Jiang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing. China
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Abu N, Rus Bakarurraini NAA, Nasir SN. Extracellular Vesicles and DAMPs in Cancer: A Mini-Review. Front Immunol 2021; 12:740548. [PMID: 34721407 PMCID: PMC8554306 DOI: 10.3389/fimmu.2021.740548] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/07/2021] [Indexed: 12/24/2022] Open
Abstract
Certain cancer therapy has been shown to induce immunogenic cell death in cancer cells and may promote tumor progression instead. The external stress or stimuli may induce cell death and contribute toward the secretion of pro inflammatory molecules. The release of damage-associated molecular patterns (DAMPs) upon induction of therapy or cell death has been shown to induce an inflammatory response. Nevertheless, the mechanism as to how the DAMPs are released and engage in such activity needs further in-depth investigation. Interestingly, some studies have shown that DAMPs can be released through extracellular vesicles (EVs) and can bind to receptors such as toll-like receptors (TCRs). Ample pre-clinical studies have shown that cancer-derived EVs are able to modulate immune responses within the tumor microenvironment. However, the information on the presence of such DAMPs within EVs is still elusive. Therefore, this mini-review attempts to summarize and appraise studies that have shown the presence of DAMPs within cancer-EVs and how it affects the downstream cellular process.
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Affiliation(s)
- Nadiah Abu
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | | | - Siti Nurmi Nasir
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
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Soliman HM, Ghonaim GA, Gharib SM, Chopra H, Farag AK, Hassanin MH, Nagah A, Emad-Eldin M, Hashem NE, Yahya G, Emam SE, Hassan AEA, Attia MS. Exosomes in Alzheimer's Disease: From Being Pathological Players to Potential Diagnostics and Therapeutics. Int J Mol Sci 2021; 22:10794. [PMID: 34639135 PMCID: PMC8509246 DOI: 10.3390/ijms221910794] [Citation(s) in RCA: 42] [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: 09/03/2021] [Revised: 10/01/2021] [Accepted: 10/01/2021] [Indexed: 12/15/2022] Open
Abstract
Exosomes (EXOs) were given attention as an extracellular vesicle (EV) with a pivotal pathophysiological role in the development of certain neurodegenerative disorders (NDD), such as Parkinson's and Alzheimer's disease (AD). EXOs have shown the potential to carry pathological and therapeutic cargo; thus, researchers have harnessed EXOs in drug delivery applications. EXOs have shown low immunogenicity as natural drug delivery vehicles, thus ensuring efficient drug delivery without causing significant adverse reactions. Recently, EXOs provided potential drug delivery opportunities in AD and promising future clinical applications with the diagnosis of NDD and were studied for their usefulness in disease detection and prediction prior to the emergence of symptoms. In the future, the microfluidics technique will play an essential role in isolating and detecting EXOs to diagnose AD before the development of advanced symptoms. This review is not reiterative literature but will discuss why EXOs have strong potential in treating AD and how they can be used as a tool to predict and diagnose this disorder.
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Affiliation(s)
- Hagar M. Soliman
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; (H.M.S.); (G.A.G.); (S.M.G.); (A.K.F.); (M.H.H.); (A.N.); (N.E.H.); (S.E.E.)
| | - Ghada A. Ghonaim
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; (H.M.S.); (G.A.G.); (S.M.G.); (A.K.F.); (M.H.H.); (A.N.); (N.E.H.); (S.E.E.)
| | - Shaza M. Gharib
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; (H.M.S.); (G.A.G.); (S.M.G.); (A.K.F.); (M.H.H.); (A.N.); (N.E.H.); (S.E.E.)
| | - Hitesh Chopra
- Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India;
| | - Aya K. Farag
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; (H.M.S.); (G.A.G.); (S.M.G.); (A.K.F.); (M.H.H.); (A.N.); (N.E.H.); (S.E.E.)
| | - Mohamed H. Hassanin
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; (H.M.S.); (G.A.G.); (S.M.G.); (A.K.F.); (M.H.H.); (A.N.); (N.E.H.); (S.E.E.)
| | - Abdalrazeq Nagah
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; (H.M.S.); (G.A.G.); (S.M.G.); (A.K.F.); (M.H.H.); (A.N.); (N.E.H.); (S.E.E.)
| | - Mahmoud Emad-Eldin
- Department of Clinical, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt;
| | - Nevertary E. Hashem
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; (H.M.S.); (G.A.G.); (S.M.G.); (A.K.F.); (M.H.H.); (A.N.); (N.E.H.); (S.E.E.)
| | - Galal Yahya
- Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt;
| | - Sherif E. Emam
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; (H.M.S.); (G.A.G.); (S.M.G.); (A.K.F.); (M.H.H.); (A.N.); (N.E.H.); (S.E.E.)
| | - Abdalla E. A. Hassan
- Applied Nucleic Acids Research Center & Chemistry, Faculty of Science, Zagazig 44519, Egypt;
| | - Mohamed S. Attia
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; (H.M.S.); (G.A.G.); (S.M.G.); (A.K.F.); (M.H.H.); (A.N.); (N.E.H.); (S.E.E.)
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Cocks A, Martinez-Rodriguez V, Del Vecchio F, Schukking M, Broseghini E, Giannakopoulos S, Fabbri M. Diverse roles of EV-RNA in cancer progression. Semin Cancer Biol 2021; 75:127-135. [PMID: 33440245 PMCID: PMC8271091 DOI: 10.1016/j.semcancer.2020.11.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 11/04/2020] [Accepted: 11/30/2020] [Indexed: 01/01/2023]
Abstract
Extracellular vesicles (EVs) have emerged as important players in all aspects of cancer biology. Their function is mediated by their cargo and surface molecules including proteins, lipids, sugars and nucleic acids. RNA in particular is a key mediator of EV function both in normal and cancer cells. This statement is supported by several lines of evidence. First, cells do not always randomly load RNA in EVs, there seems to be a specific manner in which cells populate their EVs with certain RNA molecules. Moreover, cellular uptake of EV-RNA and the secondary compartmentalization of EV-RNA in recipient cells is widely reported, and these RNAs have an impact on all aspects of cancer growth and the anti-tumoral immune response. Additionally, EV-RNA seems to work through various mechanisms of action, highlighting the intricacies of EVs and their RNA cargo as prominent means of inter-cellular communication.
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Affiliation(s)
- Alexander Cocks
- Cancer Biology Program, University of Hawai'i Cancer Center, Honolulu, HI, 96813, USA
| | - Verena Martinez-Rodriguez
- Cancer Biology Program, University of Hawai'i Cancer Center, Honolulu, HI, 96813, USA; Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawai'i at Manoa, Honolulu, HI, 96813, USA
| | - Filippo Del Vecchio
- Cancer Biology Program, University of Hawai'i Cancer Center, Honolulu, HI, 96813, USA
| | - Monique Schukking
- Cancer Biology Program, University of Hawai'i Cancer Center, Honolulu, HI, 96813, USA; Department of Molecular Biosciences & Bioengineering, University of Hawai'i at Manoa, Honolulu, HI, 96822, USA
| | - Elisabetta Broseghini
- Cancer Biology Program, University of Hawai'i Cancer Center, Honolulu, HI, 96813, USA
| | | | - Muller Fabbri
- Cancer Biology Program, University of Hawai'i Cancer Center, Honolulu, HI, 96813, USA.
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Logozzi M, Di Raimo R, Mizzoni D, Fais S. What we know on the potential use of exosomes for nanodelivery. Semin Cancer Biol 2021; 86:13-25. [PMID: 34517111 DOI: 10.1016/j.semcancer.2021.09.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 07/19/2021] [Accepted: 09/07/2021] [Indexed: 12/15/2022]
Abstract
Antitumor therapy is taking into consideration the possibility to use natural nanovesicles, called exosomes, as an ideal delivery for both old and new anti-cancer molecules. This with the attempt to improve the efficacy, at the same time reducing the systemic toxicity of physical, chemical, and biological molecules. Exosomes may in fact increase the level of biomimetism, through simulating what really occurs in nature. Although extracellularly released vesicles include both microvesicles (MVs) and exosomes, only exosomes have the size that may be considered suitable for potential use to this purpose, also by analogy with the diffusely used artificial nanoparticles, such as lyposomes. In fact, recent reports have shown that exosomes are able to interact with target cells within an organ or at a distance using different mechanisms. Much is yet to be understood about exosomes, and currently, we are looking at the visible top of an iceberg, with most of what we have to understand on these nanovesicles still under the sea. In fact, we know that exosomes released by normal cells always trigger positive effects, while those released by cells in pathological condition, such as tumors may induce undesired, dangerous, and mostly unknown effects. To date we have many pre-clinical data available and possibly useful to think about a strategic use of exosomes as a delivery nanodevice in cancer treatment. However, this review wants to critically emphasize two important points actually hampering further discussion in the field : (i) the clinical data are virtually absent at the moment ; (ii) the best cellular source of exosomes to be used to deliver drugs is really far to be defined. Facing off these two points may well facilitate the attempt to figure out this very important issue for improving at the best future anti-cancer treatments.
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Affiliation(s)
- Mariantonia Logozzi
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
| | - Rossella Di Raimo
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
| | - Davide Mizzoni
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
| | - Stefano Fais
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
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Prieto-Vila M, Yoshioka Y, Ochiya T. Biological Functions Driven by mRNAs Carried by Extracellular Vesicles in Cancer. Front Cell Dev Biol 2021; 9:620498. [PMID: 34527665 PMCID: PMC8435577 DOI: 10.3389/fcell.2021.620498] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 07/30/2021] [Indexed: 12/15/2022] Open
Abstract
Extracellular vesicles (EVs), including exosomes and microvesicles, are extracellular nanovesicles released by most cells. EVs play essential roles in intercellular communication via the transport of a large variety of lipids, proteins, and nucleic acids to recipient cells. Nucleic acids are the most commonly found molecules inside EVs, and due to their small size, microRNAs and other small RNAs are the most abundant nucleic acids. However, longer molecules, such as messenger RNAs (mRNAs), have also been found. mRNAs encapsulated within EVs have been shown to be transferred to recipient cells and translated into proteins, altering the behavior of the cells. Secretion of EVs is maintained not only through multiple normal physiological conditions but also during aberrant pathological conditions, including cancer. Recently, the mRNAs carried by EVs in cancer have attracted great interest due to their broad roles in tumor progression and microenvironmental remodeling. This review focuses on the biological functions driven by mRNAs carried in EVs in cancer, which include supporting tumor progression by activating cancer cell growth, migration, and invasion; inducing microenvironmental remodeling via hypoxia, angiogenesis, and immunosuppression; and promoting modulation of the microenvironment at distant sites for the generation of a premetastatic niche, collectively inducing metastasis. Furthermore, we describe the potential use of mRNAs carried by EVs as a noninvasive diagnostic tool and novel therapeutic approach.
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Affiliation(s)
| | | | - Takahiro Ochiya
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
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