|
1
|
Sonar S, Das A, Kalele K, Subramaniyan V. Exosome-based cancer vaccine: a cell-free approach. Mol Biol Rep 2025; 52:421. [DOI: 10.1007/s11033-025-10519-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 04/15/2025] [Indexed: 05/04/2025]
|
|
2
|
Sun MX, Zhu HC, Yu Y, Yao Y, Li HY, Feng FB, Wang QY, Liu RJ, Sun CG. Role of the Wnt signaling pathway in the complex microenvironment of breast cancer and prospects for therapeutic potential (Review). Int J Oncol 2025; 66:36. [PMID: 40145557 PMCID: PMC12068849 DOI: 10.3892/ijo.2025.5742] [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: 12/18/2024] [Accepted: 03/10/2025] [Indexed: 03/28/2025] Open
Abstract
The focus on breast cancer treatment has shifted from the cytotoxic effects of single drugs on tumor cells to multidimensional multi‑pathway synergistic intervention strategies targeting the tumor microenvironment (TME). The activation of the Wnt signaling pathway in the TME of breast cancer cells serves a key regulatory role in tissue homeostasis and is a key driver of the carcinogenic process. Modulating the crosstalk between the Wnt pathway and TME of breast cancer is key for understanding the biological behavior of breast cancer and advancing the development of novel antitumor drugs. The present review aimed to summarize the complex mechanisms of the Wnt signaling pathway in the breast cancer TME, interactions between the Wnt signaling pathway and components of the breast cancer TME and breast cancer‑associated genes, as well as the interactions between the Wnt signaling pathway and other signaling cascades at the molecular level. Furthermore, the present review aimed to highlight the unique advantages of the Wnt signaling pathway in the macro‑regulation of the TME and the current therapeutic strategies targeting the Wnt signaling pathway, their potential clinical value and future research directions in breast cancer treatment.
Collapse
Affiliation(s)
- Meng Xuan Sun
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
| | - Han Ci Zhu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
| | - Yang Yu
- State Key Laboratory of Quality Research in Chinese Medicine, and Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, P.R. China
| | - Yan Yao
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, Shandong 261000, P.R. China
| | - Hua Yao Li
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Fu Bin Feng
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, Shandong 261000, P.R. China
| | - Qing Yang Wang
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
| | - Rui Juan Liu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, Shandong 261000, P.R. China
| | - Chang Gang Sun
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, Shandong 261000, P.R. China
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| |
Collapse
|
|
3
|
Veletic I, Harris DM, Rozovski U, Bertilaccio MTS, Calin GA, Takahashi K, Li P, Liu Z, Manshouri T, Drula RC, Furudate K, Muftuoglu M, Hossain A, Wierda WG, Keating MJ, Estrov Z. CLL cell-derived exosomes alter the immune and hematopoietic systems. Leukemia 2025:10.1038/s41375-025-02590-x. [PMID: 40186065 DOI: 10.1038/s41375-025-02590-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 03/11/2025] [Accepted: 03/25/2025] [Indexed: 04/07/2025]
Abstract
The origins of immunosuppression, neutropenia, and anemia in patients with chronic lymphocytic leukemia (CLL) are not fully understood. Because in patients with CLL, circulating exosomes, which participate in cell-to-cell interactions, are CLL cell-derived, we examined whether those exosomes contribute to abnormal features of this disease. Our data revealed that CLL cell-derived exosomes engulfed by healthy donors' monocytes, fibrocytes, and lymphocytes altered target-cell gene and protein expression and suppressed normal hematopoiesis. CLL cell-derived exosomes increased normal monocytes' CD14 and CD16 expression such that it mimicked the accessory-cell profile and upregulated T cells' checkpoint PD-1 and CD160 protein levels, potentially reducing T-cell-mediated anti-CLL activity. In normal B cells, CLL cell-derived exosomes induced apoptosis and CD5 expression, suggesting that CLL cell-derived exosomes eliminate B cells and not all CD19+/CD5+ cells in CLL patients are clonal. RNA sequencing and quantitative real-time PCR revealed that CLL cell-derived exosomes harbored RNAs of pro-apoptotic genes and genes that increase metabolism, induce proliferation, and induce constitutive PI3K-mTOR pathway activation. CLL cell-derived exosomes inhibited hematopoietic progenitor proliferation, hindering the supportive effect of monocyte-derived fibrocytes. Together, our findings suggest that CLL cell-derived exosomes disrupt the immune and hematopoietic systems and contribute to disease progression in patients with CLL.
Collapse
Affiliation(s)
- Ivo Veletic
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - David M Harris
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Uri Rozovski
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel
| | - Maria Teresa S Bertilaccio
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - George A Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Koichi Takahashi
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ping Li
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Zhiming Liu
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Taghi Manshouri
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Rares-Constantin Drula
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ken Furudate
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Muharrem Muftuoglu
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anwar Hossain
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - William G Wierda
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michael J Keating
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Zeev Estrov
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| |
Collapse
|
|
4
|
He W, Cui K, Farooq MA, Huang N, Zhu S, Jiang D, Zhang X, Chen J, Liu Y, Xu G. TCR-T cell therapy for solid tumors: challenges and emerging solutions. Front Pharmacol 2025; 16:1493346. [PMID: 40129944 PMCID: PMC11931055 DOI: 10.3389/fphar.2025.1493346] [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: 09/09/2024] [Accepted: 02/20/2025] [Indexed: 03/26/2025] Open
Abstract
With the use of T cell receptor T cells (TCR-T cells) and chimeric antigen receptor T cells (CAR-T cells), T-cell immunotherapy for cancer has advanced significantly in recent years. CAR-T cell therapy has demonstrated extraordinary success when used to treat hematologic malignancies. Nevertheless, there are several barriers that prevent this achievement from being applied to solid tumors, such as challenges with tumor targeting and inadequate transit and adaption of genetically modified T-cells, especially in unfavorable tumor microenvironments The deficiencies of CAR-T cell therapy in the treatment of solid tumors are compensated for by TCR-T cells, which have a stronger homing ability to initiate intracellular commands, 90% of the proteins can be used as developmental targets, and they can recognize target antigens more broadly. As a result, TCR-T cells may be more effective in treating solid tumors. In this review, we discussed the structure of TCR-T and have outlined the drawbacks of TCR-T in cancer therapy, and suggested potential remedies. This review is crucial in understanding the current state and future potential of TCR-T cell therapy. We emphasize how important it is to use combinatorial approaches, combining new combinations of various emerging strategies with over-the-counter therapies designed for TCR-T, to increase the anti-tumor efficacy of TCR-T inside the TME and maximize treatment safety, especially when it comes to solid tumor immunotherapies.
Collapse
Affiliation(s)
- Wanjun He
- Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, The First Dongguan Affiliated Hospital, School of Medical Technology, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Molecular Immunology and Cell Therapy, Guangdong Medical University, Dongguan, China
| | - Kai Cui
- Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, The First Dongguan Affiliated Hospital, School of Medical Technology, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Molecular Immunology and Cell Therapy, Guangdong Medical University, Dongguan, China
| | - Muhammad Asad Farooq
- Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, The First Dongguan Affiliated Hospital, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Na Huang
- Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, The First Dongguan Affiliated Hospital, School of Medical Technology, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Molecular Immunology and Cell Therapy, Guangdong Medical University, Dongguan, China
| | - Songshan Zhu
- Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, The First Dongguan Affiliated Hospital, School of Medical Technology, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Molecular Immunology and Cell Therapy, Guangdong Medical University, Dongguan, China
| | - Dan Jiang
- Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, The First Dongguan Affiliated Hospital, School of Medical Technology, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Molecular Immunology and Cell Therapy, Guangdong Medical University, Dongguan, China
| | - Xiqian Zhang
- Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, The First Dongguan Affiliated Hospital, School of Medical Technology, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Molecular Immunology and Cell Therapy, Guangdong Medical University, Dongguan, China
- Yinchuan Guolong Orthopedic Hospital, Yinchuan, China
| | - Jian Chen
- Yinchuan Guolong Orthopedic Hospital, Yinchuan, China
| | - Yinxia Liu
- Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, The First Dongguan Affiliated Hospital, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Guangxian Xu
- Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, The First Dongguan Affiliated Hospital, School of Medical Technology, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Molecular Immunology and Cell Therapy, Guangdong Medical University, Dongguan, China
| |
Collapse
|
|
5
|
Hashemi M, Khosroshahi EM, Daneii P, Hassanpoor A, Eslami M, Koohpar ZK, Asadi S, Zabihi A, Jamali B, Ghorbani A, Nabavi N, Memarkashani MR, Salimimoghadam S, Taheriazam A, Tan SC, Entezari M, Farahani N, Hushmandi K. Emerging roles of CircRNA-miRNA networks in cancer development and therapeutic response. Noncoding RNA Res 2025; 10:98-115. [PMID: 39351450 PMCID: PMC11440256 DOI: 10.1016/j.ncrna.2024.09.006] [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: 02/23/2024] [Revised: 07/18/2024] [Accepted: 09/03/2024] [Indexed: 10/04/2024] Open
Abstract
The complex interplay of epigenetic factors is essential in regulating the hallmarks of cancer and orchestrating intricate molecular interactions during tumor progression. Circular RNAs (circRNAs), known for their covalently closed loop structures, are non-coding RNA molecules exceptionally resistant to enzymatic degradation, which enhances their stability and regulatory functions in cancer. Similarly, microRNAs (miRNAs) are endogenous non-coding RNAs with linear structures that regulate cellular biological processes akin to circRNAs. Both miRNAs and circRNAs exhibit aberrant expressions in various cancers. Notably, circRNAs can function as sponges for miRNAs, influencing their activity. The circRNA/miRNA interaction plays a pivotal role in the regulation of cancer progression, including in brain, gastrointestinal, gynecological, and urological cancers, influencing key processes such as proliferation, apoptosis, invasion, autophagy, epithelial-mesenchymal transition (EMT), and more. Additionally, this interaction impacts the response of tumor cells to radiotherapy and chemotherapy and contributes to immune evasion, a significant challenge in cancer therapy. Both circRNAs and miRNAs hold potential as biomarkers for cancer prognosis and diagnosis. In this review, we delve into the circRNA-miRNA circuit within human cancers, emphasizing their role in regulating cancer hallmarks and treatment responses. This discussion aims to provide insights for future research to better understand their functions and potentially guide targeted treatments for cancer patients using circRNA/miRNA-based strategies.
Collapse
Affiliation(s)
- Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elaheh Mohandesi Khosroshahi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Pouria Daneii
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Aria Hassanpoor
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maedeh Eslami
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Zeinab Khazaei Koohpar
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
| | - Saba Asadi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Abbas Zabihi
- Department of Biology, Faculty of Basic Sciences, Islamic Azad University, Hamedan Branch, Hamedan, Iran
| | - Behdokht Jamali
- Department of Microbiology and Genetics, Kherad Institute of Higher Education, Bushehr, Iran
| | - Amin Ghorbani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia, V8V 1P7, Canada
| | | | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Shing Cheng Tan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Kiavash Hushmandi
- Department of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| |
Collapse
|
|
6
|
Lach MS, Wróblewska JP, Michalak M, Budny B, Wrotkowska E, Suchorska WM. The Effect of Ionising Radiation on the Properties of Tumour-Derived Exosomes and Their Ability to Modify the Biology of Non-Irradiated Breast Cancer Cells-An In Vitro Study. Int J Mol Sci 2025; 26:376. [PMID: 39796230 PMCID: PMC11719956 DOI: 10.3390/ijms26010376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 12/30/2024] [Accepted: 01/02/2025] [Indexed: 01/13/2025] Open
Abstract
The vast majority of breast cancer patients require radiotherapy but some of them will develop local recurrences and potentially metastases in the future. Recent data show that exosomal cargo is essential in these processes. Thus, we investigated the influence of ionising radiation on exosome properties and their ability to modify the sensitivity and biology of non-irradiated cells. Exosomes were isolated from breast cancer cell lines (MDA-MB-231, MCF7, and SKBR3) irradiated with 2 Gy (Exo 2 Gy) or no irradiation (Exo 0 Gy). Despite some differences in their molecular profiles, they did not affect cell viability, proliferation, cell cycle phase distribution, and radioresistance; however, both populations showed the ability to modify cell migration and invasion potential, as confirmed by the downregulation of β-catenin, which is responsible for maintaining the epithelial phenotype. Interestingly, exosomes from irradiated BCa cells were more actively deposited in the endothelial cells (EA.hy926). Furthermore, exosomes tend to lower the expression of CD31, which is responsible for maintaining intact vascularity. This preliminary study demonstrates the vital role of exosomes and their altered profile due to irradiation in the pathobiology of breast cancer.
Collapse
Affiliation(s)
- Michał Stefan Lach
- Department of Electroradiology, Poznan University of Medical Sciences, Garbary 15, 61-866 Poznan, Poland;
- Radiobiology Lab, The Greater Poland Cancer Centre, Garbary 15 Street, 61-866 Poznan, Poland
| | - Joanna Patrycja Wróblewska
- Department of Life Sciences and Medicine (DLSM), University of Luxembourg, 6, Avenue du Swing, 4367 Belvaux, Luxembourg;
| | - Marcin Michalak
- Surgical, Oncological and Endoscopic Gynaecology Department, The Greater Poland Cancer Centre, Garbary 15 Street, 61-866 Poznan, Poland;
| | - Bartłomiej Budny
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, Przybyszewskiego 49 Street, 60-355 Poznan, Poland; (B.B.); (E.W.)
| | - Elżbieta Wrotkowska
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, Przybyszewskiego 49 Street, 60-355 Poznan, Poland; (B.B.); (E.W.)
| | - Wiktoria Maria Suchorska
- Department of Electroradiology, Poznan University of Medical Sciences, Garbary 15, 61-866 Poznan, Poland;
- Radiobiology Lab, The Greater Poland Cancer Centre, Garbary 15 Street, 61-866 Poznan, Poland
| |
Collapse
|
|
7
|
Das A, Sonar S, Kalele K, Subramaniyan V. Fruit exosomes: a sustainable green cancer therapeutic. SUSTAINABLE FOOD TECHNOLOGY 2025; 3:145-160. [DOI: 10.1039/d4fb00281d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2024]
Abstract
Fruit exosomes are the source of natural cancer therapeutic tools.
Collapse
Affiliation(s)
- Asmit Das
- Center for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, India
| | - Swarup Sonar
- Center for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, India
| | - Ketki Kalele
- Department of Oncology, Neuron Institute of Applied Research, Amravati, Maharashtra, India
| | - Vetriselvan Subramaniyan
- Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Bandar Sunway, 47500 Subang Jaya, Selangor, Malaysia
| |
Collapse
|
|
8
|
Rana R, Devi SN, Bhardwaj AK, Yashavarddhan MH, Bohra D, Ganguly NK. Exosomes as nature's nano carriers: Promising drug delivery tools and targeted therapy for glioma. Biomed Pharmacother 2025; 182:117754. [PMID: 39731936 DOI: 10.1016/j.biopha.2024.117754] [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: 09/09/2024] [Revised: 11/28/2024] [Accepted: 12/09/2024] [Indexed: 12/30/2024] Open
Abstract
Exosomes, minute vesicles originating from diverse cell types, exhibit considerable potential as carriers for drug delivery in glioma therapy. These naturally occurring nanocarriers facilitate the transfer of proteins, RNAs, and lipids between cells, offering advantages such as biocompatibility, efficient cellular absorption, and the capability to traverse the blood-brain barrier (BBB). In the realm of cancer, particularly gliomas, exosomes play pivotal roles in modulating tumor growth, regulating immunity, and combating drug resistance. Moreover, exosomes serve as valuable biomarkers for diagnosing diseases and assessing prognosis. This review aims to elucidate the therapeutic and diagnostic promise of exosomes in glioma treatment, highlighting the innovative advances in exosome engineering that enable precise drug loading and targeting. By circumventing challenges associated with current glioma treatments, exosome-mediated drug delivery strategies can enhance the efficacy of chemotherapy drugs like temozolomide and overcome drug resistance mechanisms. This review underscores the multifaceted roles of exosomes in glioma pathogenesis and therapy, underscoring their potential as natural nanocarriers for targeted therapy and heralding a new era of hope for glioma treatment.
Collapse
Affiliation(s)
- Rashmi Rana
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India.
| | | | - Amit Kumar Bhardwaj
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - M H Yashavarddhan
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Deepika Bohra
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Nirmal Kumar Ganguly
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| |
Collapse
|
|
9
|
Qiu L, Ma Z, Wu X. Mutant p53-Mediated Tumor Secretome: Bridging Tumor Cells and Stromal Cells. Genes (Basel) 2024; 15:1615. [PMID: 39766882 PMCID: PMC11675497 DOI: 10.3390/genes15121615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 12/06/2024] [Accepted: 12/16/2024] [Indexed: 01/11/2025] Open
Abstract
The tumor secretome comprises the totality of protein factors secreted by various cell components within the tumor microenvironment, serving as the primary medium for signal transduction between tumor cells and between tumor cells and stromal cells. The deletion or mutation of the p53 gene leads to alterations in cellular secretion characteristics, contributing to the construction of the tumor microenvironment in a cell non-autonomous manner. This review discusses the critical roles of mutant p53 in regulating the tumor secretome to remodel the tumor microenvironment, drive tumor progression, and influence the plasticity of cancer-associated fibroblasts (CAFs) as well as the dynamics of tumor immunity by focusing on both secreted protein expression and secretion pathways. The aim is to provide new insights for targeted cancer therapies.
Collapse
Affiliation(s)
| | | | - Xiaoming Wu
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Chenggong Campus, 727 South Jingming Road, Kunming 650500, China; (L.Q.); (Z.M.)
| |
Collapse
|
|
10
|
Asadi M, Zafari V, Sadeghi-Mohammadi S, Shanehbandi D, Mert U, Soleimani Z, Caner A, Zarredar H. The role of tumor microenvironment and self-organization in cancer progression: Key insights for therapeutic development. BIOIMPACTS : BI 2024; 15:30713. [PMID: 40256216 PMCID: PMC12008505 DOI: 10.34172/bi.30713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 10/08/2024] [Accepted: 11/20/2024] [Indexed: 04/22/2025]
Abstract
Introduction The tumor microenvironment (TME) plays a pivotal role in cancer progression, influencing tumor initiation, growth, invasion, metastasis, and response to therapies. This study explores the dynamic interactions within the TME, particularly focusing on self-organization-a process by which tumor cells and their microenvironment reciprocally shape one another, leading to cancer progression and resistance. Understanding these interactions can reveal new prognostic markers and therapeutic targets within the TME, such as extracellular matrix (ECM) components, immune cells, and cytokine signaling pathways. Methods A comprehensive search method was employed to investigate the current academic literature on TME, particularly focusing on self-organization in the context of cancer progression and resistance across the PubMed, Google Scholar, and Science Direct databases. Results Recent studies suggest that therapies that disrupt TME self-organization could improve patient outcomes by defeating drug resistance and increasing the effectiveness of conventional therapy. Additionally, this research highlights the essential of understanding the biophysical properties of the TME, like cytoskeletal alterations, in the development of more effective malignancy therapy. Conclusion This review indicated that targeting the ECM and immune cells within the TME can improve therapy effectiveness. Also, by focusing on TME self-organization, we can recognize new therapeutic plans to defeat drug resistance.
Collapse
Affiliation(s)
- Milad Asadi
- Department of Basic Oncology, Ege University, Institute of Health Sciences, Izmir, Turkey
| | - Venus Zafari
- Department of Basic Oncology, Ege University, Institute of Health Sciences, Izmir, Turkey
| | - Sanam Sadeghi-Mohammadi
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ufuk Mert
- Institute of Health Sciences, Department of Basic Oncology, Ege University, Izmir, Turkey
| | - Zahra Soleimani
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ayşe Caner
- Department of Basic Oncology, Ege University, Institute of Health Sciences, Izmir, Turkey
| | - Habib Zarredar
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
11
|
Shi K, Fu W, Farhadi Sabet Z, Ye J, Liang S, Liu T, Liu Q, Guo M, You M, Wu J, Bai R, Liu Y, Hu B, Cui X, Li J, Chen C. Hydrogel-Mediated Jamming of Exosome Communications That Counter Tumor Adaption in the Tumor Immune Microenvironment. ACS NANO 2024; 18:33042-33057. [PMID: 39441690 DOI: 10.1021/acsnano.4c07603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
Hypoxia, a common occurrence within solid tumors, can stimulate the dissemination of deceptive tumor exosomes, which function as communicative bridges and orchestrate the recruitment of various supportive cell types for enhanced tumor adaptability in a tumor immune microenvironment. Current nanotechnology provides us intelligent strategies to combat the hypoxic tumor microenvironment. However, once exposed to external stimuli, such as chemotherapy, tumor cells simultaneously release malignant signals to develop tumor migration and immunosuppression, posing challenges to clinical practice. Taking advantage of the membrane-targeting therapeutic strategy, the application of a self-assembled short peptide (PepABS-py), affording hydrogels on tumor cell surfaces, can block exosome dissemination with fiber-like nanostructures and effectively limit the systemic adverse effects of traditional therapeutics. Moreover, PepABS-py can attenuate the hypoxic tumor microenvironment in vivo by carrying an inhibitor of the hypoxic tumor-overexpressed CA IX enzyme, where hypoxia is also a crucial regulator to induce tumor exosomes and mediate intercellular communications within the immune system. Herein, its application on jamming exosome communications can target the T cell-related signaling pathway by regulating microRNAs in exosome cargoes and ultimately enhances CD8+ T cell infiltration and alleviates inflammatory monocytes at metastasis sites. Collectively, with the capability of blocking exosome dissemination, PepABS-py can be applied as a promising tumor membrane-targeting therapeutic tool to counter tumor adaption within an immune microenvironment and further advance traditional chemotherapy.
Collapse
Affiliation(s)
- Kejian Shi
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, New Cornerstone Science Laboratory, National Center for Nanoscience and Technology of China, Beijing 100190, People's Republic of China
| | - Wenjiao Fu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, New Cornerstone Science Laboratory, National Center for Nanoscience and Technology of China, Beijing 100190, People's Republic of China
- Sino-Danish College, Sino-Danish Center for Education and Research, University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China
| | - Zeinab Farhadi Sabet
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, New Cornerstone Science Laboratory, National Center for Nanoscience and Technology of China, Beijing 100190, People's Republic of China
| | - Jinmin Ye
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, New Cornerstone Science Laboratory, National Center for Nanoscience and Technology of China, Beijing 100190, People's Republic of China
| | - Shijian Liang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, New Cornerstone Science Laboratory, National Center for Nanoscience and Technology of China, Beijing 100190, People's Republic of China
| | - Tao Liu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, New Cornerstone Science Laboratory, National Center for Nanoscience and Technology of China, Beijing 100190, People's Republic of China
| | - Qiaolin Liu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, New Cornerstone Science Laboratory, National Center for Nanoscience and Technology of China, Beijing 100190, People's Republic of China
| | - Mengyu Guo
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, New Cornerstone Science Laboratory, National Center for Nanoscience and Technology of China, Beijing 100190, People's Republic of China
| | - Min You
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, New Cornerstone Science Laboratory, National Center for Nanoscience and Technology of China, Beijing 100190, People's Republic of China
| | - Junguang Wu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, New Cornerstone Science Laboratory, National Center for Nanoscience and Technology of China, Beijing 100190, People's Republic of China
| | - Ru Bai
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, New Cornerstone Science Laboratory, National Center for Nanoscience and Technology of China, Beijing 100190, People's Republic of China
| | - Ying Liu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, New Cornerstone Science Laboratory, National Center for Nanoscience and Technology of China, Beijing 100190, People's Republic of China
| | - Bin Hu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, New Cornerstone Science Laboratory, National Center for Nanoscience and Technology of China, Beijing 100190, People's Republic of China
| | - Xuejing Cui
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, New Cornerstone Science Laboratory, National Center for Nanoscience and Technology of China, Beijing 100190, People's Republic of China
| | - Jiayang Li
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, New Cornerstone Science Laboratory, National Center for Nanoscience and Technology of China, Beijing 100190, People's Republic of China
| | - Chunying Chen
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, New Cornerstone Science Laboratory, National Center for Nanoscience and Technology of China, Beijing 100190, People's Republic of China
- Sino-Danish College, Sino-Danish Center for Education and Research, University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China
- Research Unit of Nanoscience and Technology, Chinese Academy of Medical Sciences, Beijing 100021, People's Republic of China
| |
Collapse
|
|
12
|
Yan H, Cai X, Zhang J, Zhao H, Wu H, Zhang J, Xu L, Liu S, Zang Y, Fu S. Gastric cancer cell-derived exosomal miRNA-128-3p promotes angiogenesis by targeting SASH1. Front Oncol 2024; 14:1440996. [PMID: 39664191 PMCID: PMC11631727 DOI: 10.3389/fonc.2024.1440996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 11/11/2024] [Indexed: 12/13/2024] Open
Abstract
Exosomes, key components of the tumour microenvironment, can mediate intercellular communication through the delivery of various signalling molecules, including microribonucleic acids (miRNAs), and ultimately participate in regulating the process of tumour development. In this study, we aimed to investigate the reason and mechanism by which exosomal miRNAs derived from gastric cancer cells affect carcinogenesis and metastasis. Among these miRNAs, microRNA-128-3p (miR-128-3p) was highly expressed in serum exosomes isolated from gastric cancer patients, as confirmed by high-throughput sequencing and subsequent experiments. Coculture of gastric cancer-derived exosomes overexpressing miR-128-3p with human umbilical vein endothelial cells (HUVECs) significantly enhanced HUVEC proliferation, migratio n and angiogenesis. Bioinformatics analysis suggested SASH1 as the target gene of miR-128-3p. The dual luciferase assay and Western blot analysis results confirmed that miR-128-3p directly targeted SASH1 to inhibit its expression in HUVECs. Therefore, this study provides preliminary evidence that gastric cancer-derived exosomal miR-128-3p promotes tumour angiogenesis by targeting SASH1, reveals the potential diagnostic and therapeutic value of cancer-derived exosomal miR-128-3p, and provides new insights into the novel molecular mechanisms regulating metastasis. This study provides further information for understanding the role of gastric cancer-derived exosomal miR-128-3p in cancer progression and to discover new therapeutic targets.
Collapse
Affiliation(s)
- Hao Yan
- Department of Gastroenterology, Shandong Public Health Clinical Center, Shandong University, Jinan, China
| | - Xinyu Cai
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
- Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Jianna Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Hongpeng Zhao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Hongwen Wu
- Department of Gastroenterology, Shandong Public Health Clinical Center, Shandong University, Jinan, China
| | - Jingbo Zhang
- Department of Gastroenterology, Shandong Public Health Clinical Center, Shandong University, Jinan, China
| | - Lanzhi Xu
- Department of Gastroenterology, Shandong Public Health Clinical Center, Shandong University, Jinan, China
| | - Shizheng Liu
- Department of Gastroenterology, Shandong Public Health Clinical Center, Shandong University, Jinan, China
| | - Yuanwei Zang
- Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shanshan Fu
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| |
Collapse
|
|
13
|
Zhang SH, Peng LL, Chen YF, Xu Y, Moradi V. Focusing on exosomes to overcome the existing bottlenecks of CAR-T cell therapy. Inflamm Regen 2024; 44:45. [PMID: 39490997 PMCID: PMC11533312 DOI: 10.1186/s41232-024-00358-x] [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: 07/15/2024] [Accepted: 10/22/2024] [Indexed: 11/05/2024] Open
Abstract
Since chimeric antigen receptor T (CAR-T) cells were introduced three decades ago, the treatment using these cells has led to outstanding outcomes, and at the moment, CAR-T cell therapy is a well-established mainstay for treating CD19 + malignancies and multiple myeloma. Despite the astonishing results of CAR-T cell therapy in B-cell-derived malignancies, several bottlenecks must be overcome to promote its safety and efficacy and broaden its applicability. These bottlenecks include cumbersome production process, safety concerns of viral vectors, poor efficacy in treating solid tumors, life-threatening side effects, and dysfunctionality of infused CAR-T cells over time. Exosomes are nano-sized vesicles that are secreted by all living cells and play an essential role in cellular crosstalk by bridging between cells. In this review, we discuss how the existing bottlenecks of CAR-T cell therapy can be overcome by focusing on exosomes. First, we delve into the effect of tumor-derived exosomes on the CAR-T cell function and discuss how inhibiting their secretion can enhance the efficacy of CAR-T cell therapy. Afterward, the application of exosomes to the manufacturing of CAR-T cells in a non-viral approach is discussed. We also review the latest advancements in ex vivo activation and cultivation of CAR-T cells using exosomes, as well as the potential of engineered exosomes to in vivo induction or boost the in vivo proliferation of CAR-T cells. Finally, we discuss how CAR-engineered exosomes can be used as a versatile tool for the direct killing of tumor cells or delivering intended therapeutic payloads in a targeted manner.
Collapse
Affiliation(s)
- Si-Heng Zhang
- Faculty of Medicine, Macau University of Science and Technology, Taipa, Macao SAR, 999078, China
- Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, Zhejiang, 310000, China
| | - Ling-Long Peng
- Wuhu Hospital, East China Normal University (The Second People's Hospital of Wuhu), Wuhu, 241000, China
| | - Yi-Fei Chen
- Faculty of Medicine, Macau University of Science and Technology, Taipa, Macao SAR, 999078, China
| | - Yan Xu
- Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, Zhejiang, 310000, China.
| | - Vahid Moradi
- Hematology and Bood Transfusion Science Department, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
14
|
Akla N, Veilleux C, Annabi B. The Chemopreventive Impact of Diet-Derived Phytochemicals on the Adipose Tissue and Breast Tumor Microenvironment Secretome. Nutr Cancer 2024; 77:9-25. [PMID: 39300732 DOI: 10.1080/01635581.2024.2401647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 08/30/2024] [Accepted: 09/02/2024] [Indexed: 09/22/2024]
Abstract
Cancer cells-derived extracellular vesicles can trigger the transformation of adipose-derived mesenchymal stem cells (ADMSC) into a pro-inflammatory, cancer-associated adipocyte (CAA) phenotype. Such secretome-mediated crosstalk between the adipose tissue and the tumor microenvironment (TME) therefore impacts tumor progression and metastatic processes. In addition, emerging roles of diet-derived phytochemicals, especially epigallocatechin-3-gallate (EGCG) among other polyphenols, in modulating exosome-mediated metabolic and inflammatory signaling pathways have been highlighted. Here, we discuss how selected diet-derived phytochemicals could alter the secretome signature as well as the crosstalk dynamics between the adipose tissue and the TME, with a focus on breast cancer. Their broader implication in the chemoprevention of obesity-related cancers is also discussed.
Collapse
Affiliation(s)
- Naoufal Akla
- Laboratoire d'Oncologie Moléculaire, Département de Chimie and CERMO-FC, Université du Québec à Montréal, Montreal, Canada
| | - Carolane Veilleux
- Laboratoire d'Oncologie Moléculaire, Département de Chimie and CERMO-FC, Université du Québec à Montréal, Montreal, Canada
| | - Borhane Annabi
- Laboratoire d'Oncologie Moléculaire, Département de Chimie and CERMO-FC, Université du Québec à Montréal, Montreal, Canada
| |
Collapse
|
|
15
|
Shang H, Lu L, Fan M, Lu Y, Shi X, Lu H. Exosomal circHIF1A derived from hypoxic-induced carcinoma-associated fibroblasts promotes hepatocellular carcinoma cell malignant phenotypes and immune escape. Int Immunopharmacol 2024; 138:112282. [PMID: 38936058 DOI: 10.1016/j.intimp.2024.112282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 05/06/2024] [Accepted: 05/14/2024] [Indexed: 06/29/2024]
Abstract
Hypoxia is a hallmark of solid tumors. Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment, and CAF-derived exosomes are involved in cancer genesis and progression. Here, this work investigated the role and mechanism of exosomal circHIF1A derived from hypoxia-induced CAFs in hepatocellular carcinoma (HCC) tumorigenesis. CAFs isolated from fresh HCC tissues were incubated in normoxia or hypoxia condition (N/CAFs or H/CAFs), and then the exosomes from N/CAFs or H/CAFs were isolated for functional analysis. Cell proliferation, migration and invasion were analyzed by cell counting kit-8, colony formation, and transwell assays. Immune evasion was evaluated by measuring the cytotoxicity and viability of CD8+T cells. qRT-PCR and western blotting analyses were used for the level measurement of genes and proteins. The binding between Hu antigen R (HuR) and circHIF1A or Programmed death ligand 1 (PD-L1) was analyzed by RNA immunoprecipitation assay. Functionally, we found that CAFs, especially CAFs under hypoxic stress (H/CAFs), promoted the proliferation, migration, invasion and EMT progression in HCC cells, as well as induced immune escape by suppressing CD8+T cell cytotoxicity and activity in an exosome-dependent manner. H/CAFs-derived exosomes showed highly expressed circHIF1A, and could secrete circHIF1A into HCC cells via exosomes. The oncogenic effects of H/CAFs-secreted exosomes were abolished by circHIF1A knockdown. Mechanistically, circHIF1A interacted with HuR to stabilize PD-L1 expression in HCC cells. Meanwhile, circHIF1A silencing suppressed HCC cell proliferation, mobility and immune escape by regulating PD-L1 expression. In all, exosomal circHIF1A derived from hypoxic-induced CAFs promoted the proliferation, migration, invasion, EMT progression and immune escape in HCC cells by up-regulating PD-L1 expression in a HuR-dependent manner.
Collapse
Affiliation(s)
- Hao Shang
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an City 710004, Shaanxi, China
| | - Le Lu
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an City 710004, Shaanxi, China
| | - Meng Fan
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an City 710004, Shaanxi, China
| | - Yuxuan Lu
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an City 710004, Shaanxi, China
| | - Xiali Shi
- Department of Anesthesiology and Operation, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an City 710004, Shaanxi, China
| | - Hongwei Lu
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an City 710004, Shaanxi, China.
| |
Collapse
|
|
16
|
Ren H, Wang M, Ma X, An L, Guo Y, Ma H. METTL3 in cancer-associated fibroblasts-derived exosomes promotes the proliferation and metastasis and suppresses ferroptosis in colorectal cancer by eliciting ACSL3 m6A modification. Biol Direct 2024; 19:68. [PMID: 39160584 PMCID: PMC11331890 DOI: 10.1186/s13062-024-00511-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 08/08/2024] [Indexed: 08/21/2024] Open
Abstract
BACKGROUND Cancer-associated fibroblasts (CAFs) have been reported that can affect cancer cell proliferation, metastasis, ferroptosis, and immune escape. METTL3-mediated N6-methyladenine (m6A) modification is involved in the tumorigenesis of colorectal cancer (CRC). Herein, we investigated whether METTL3-dependent m6A in CAFs-derived exosomes (exo) affected CRC progression. METHODS qRT-PCR and western blotting analyses detected levels of mRNAs and proteins. Cell proliferation and metastasis were evaluated using MTT, colony formation, transwell, and wound healing assays, respectively. Cell ferroptosis was assessed by detecting cell viability and the levels of Fe+, reactive oxygen species, and glutathione after erastin treatment. Exosomes were isolated from CAFs by ultracentrifugation. The m6A modification profile was determined by methylated RNA immunoprecipitation assay and the interaction between METTL3 and ACSL3 (acyl-CoA synthetase 3) was verified using dual-luciferase reporter assay. Animal models were established for in vivo analysis. RESULTS CAFs promoted CRC cell proliferation and metastasis, and suppressed cell ferroptosis. METTL3 was enriched in CAFs and was packaged into exosomes. The m6A modification and METTL3 expression were increased in CRC samples. Knockdown of METTL3 in CAFs-exo suppressed CRC cell proliferation and metastasis, and induced cell ferroptosis. Mechanistically, METTL3 induced ACSL3 m6A modification and stabilized its expression. The anticancer effects mediated by METTL3-silenced CAFs-exo could be rescued by ACSL3 overexpression. Moreover, in vivo assay also showed that CAFs-exo with decreased METTL3 could hinder CRC growth and metastasis in mice models. CONCLUSION CAFs promoted the proliferation and metastasis, and restrained the ferroptosis in CRC by exosomal METTL3-elicited ACSL3 m6A modification.
Collapse
Affiliation(s)
- Hongtao Ren
- Department of Radiotherapy, Second Affiliated Hospital of Xi'an Jiaotong University, No. 57, Siwu Road, Xi'an City, Shaanxi, 710004, China
| | - Mincong Wang
- Department of Radiotherapy, Second Affiliated Hospital of Xi'an Jiaotong University, No. 57, Siwu Road, Xi'an City, Shaanxi, 710004, China
| | - Xiulong Ma
- Department of Radiotherapy, Second Affiliated Hospital of Xi'an Jiaotong University, No. 57, Siwu Road, Xi'an City, Shaanxi, 710004, China
| | - Lei An
- Department of Radiotherapy, Second Affiliated Hospital of Xi'an Jiaotong University, No. 57, Siwu Road, Xi'an City, Shaanxi, 710004, China
| | - Yuyan Guo
- Department of Radiotherapy, Second Affiliated Hospital of Xi'an Jiaotong University, No. 57, Siwu Road, Xi'an City, Shaanxi, 710004, China
| | - Hongbing Ma
- Department of Radiotherapy, Second Affiliated Hospital of Xi'an Jiaotong University, No. 57, Siwu Road, Xi'an City, Shaanxi, 710004, China.
| |
Collapse
|
|
17
|
Mafi A, Hedayati N, Milasi YE, Kahkesh S, Daviran M, Farahani N, Hashemi M, Nabavi N, Alimohammadi M, Rahimzadeh P, Taheriazam A. The function and mechanism of circRNAs in 5-fluorouracil resistance in tumors: Biological mechanisms and future potential. Pathol Res Pract 2024; 260:155457. [PMID: 39018926 DOI: 10.1016/j.prp.2024.155457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 07/04/2024] [Accepted: 07/05/2024] [Indexed: 07/19/2024]
Abstract
5-Fluorouracil (5-FU) is a well-known chemotherapy drug extensively used in the treatment of breast cancer. It works by inhibiting cancer cell proliferation and inducing cell death through direct incorporation into DNA and RNA via thymidylate synthase (TS). Circular RNAs (circRNAs), a novel family of endogenous non-coding RNAs (ncRNAs) with limited protein-coding potential, contribute to 5-FU resistance. Their identification and targeting are crucial for enhancing chemosensitivity. CircRNAs can regulate tumor formation and invasion by adhering to microRNAs (miRNAs) and interacting with RNA-binding proteins, regulating transcription and translation. MiRNAs can influence enzymes responsible for 5-FU metabolism in cancer cells, affecting their sensitivity or resistance to the drug. In the context of 5-FU resistance, circRNAs can target miRNAs and regulate biological processes such as cell proliferation, cell death, glucose metabolism, hypoxia, epithelial-to-mesenchymal transition (EMT), and drug efflux. This review focuses on the function of circRNAs in 5-FU resistance, discussing the underlying molecular pathways and biological mechanisms. It also presents recent circRNA/miRNA-targeted cancer therapeutic strategies for future clinical application.
Collapse
Affiliation(s)
- Alireza Mafi
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran; Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Neda Hedayati
- School of Medicine, Iran University of Medical Science, Tehran, Iran
| | - Yaser Eshaghi Milasi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Samaneh Kahkesh
- Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Minoo Daviran
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Najma Farahani
- Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia V8V 1P7, Canada
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| |
Collapse
|
|
18
|
Fan Y, Yu Y. Cancer-associated fibroblasts-derived exosomal METTL3 promotes the proliferation, invasion, stemness and glutaminolysis in non-small cell lung cancer cells by eliciting SLC7A5 m6A modification. Hum Cell 2024; 37:1120-1131. [PMID: 38625505 DOI: 10.1007/s13577-024-01056-z] [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: 11/17/2023] [Accepted: 03/13/2024] [Indexed: 04/17/2024]
Abstract
Cancer-associated fibroblasts (CAFs) can promote the crosstalk between cancer cells and tumor microenvironment by exosomes. METTL3-mediated N6-methyladenine (m6A) modification has been proved to promote the progression of non-small cell lung cancer (NSCLC). Here, we focused on the impacts of CAFs-derived exosomes and METTL3-mediated m6A modification on NSCLC progression. Functional analyses were conducted using Cell Counting Kit-8, EdU, colony formation, sphere formation and transwell assays, respectively. Glutamine metabolism was evaluated by detecting glutamate consumption, and the production of intercellular glutamate and α-ketoglutarate (α-KG). qRT-PCR and western blotting analyses were utilized to measure the levels of genes and proteins. Exosomes were isolated by kits. The methylated RNA immunoprecipitation assay detected the m6A modification profile of Amino acid transporter LAT1 (SLC7A5) mRNA. The NSCLC mouse model was established to conduct in vivo experiments. We found that CAFs promoted the proliferation, invasion, stemness and glutaminolysis in NSCLC cells. METTL3 was enriched in CAFs and was packaged into exosomes. After knockdown of METTL3 in CAF exosomes, it was found the oncogenic effects of CAFs on NSCLC cells were suppressed. CAFs elevated m6A levels in NSCLC cells. Mechanistically, exosomal METTL3-induced m6A modification in SLC7A5 mRNA and stabilized its expression in NSCLC cells. Moreover, SLC7A5 overexpression abolished the inhibitory effects of exosomal METTL3-decreased CAFs on NSCLC cells. In addition, METTL3 inhibition in CAF exosomes impeded NSCLC growth in vivo. In all, CAFs-derived exosomal METTL3 promoted the proliferation, invasion, stemness and glutaminolysis in NSCLC cells by inducing SLC7A5 m6A modification.
Collapse
Affiliation(s)
- Yafeng Fan
- Department of Respiratory Medicine, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, No. 3, Zhigongxin Street, Xinghualing District, Taiyuan, 030000, China
| | - Yanling Yu
- Biotherapy department, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, 030000, China.
| |
Collapse
|
|
19
|
Sha G, Zhang W, Jiang Z, Zhao Q, Wang D, Tang D. Exosomal non-coding RNA: A new frontier in diagnosing and treating pancreatic cancer: A review. Int J Biol Macromol 2024; 263:130149. [PMID: 38365161 DOI: 10.1016/j.ijbiomac.2024.130149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 01/27/2024] [Accepted: 02/11/2024] [Indexed: 02/18/2024]
Abstract
Pancreatic cancer is the most fatal malignancy worldwide. Once diagnosed, most patients are already at an advanced stage because of their highly heterogeneous, drug-resistant, and metastatic nature and the lack of effective diagnostic markers. Recently, the study of proliferation, metastasis, and drug resistance mechanisms in pancreatic cancer and the search for useful diagnostic markers have posed significant challenges to the scientific community. Exosomes carry various biomolecules (DNA, non-coding RNAs (ncRNAs), proteins, and lipids) that mediate communication between tumors and other cells. ncRNAs can be transported through exosomes to numerous relevant receptor cells and regulate local epithelial-mesenchymal transition (EMT) in tumor tissue, proliferation, drug resistance, and the establishment of pre-metastatic ecological niches in distant organs. In summary, exosomal ncRNAs promote tumor cell proliferation, invasion, and metastasis through multiple EMT, immunosuppression, angiogenesis, and extracellular matrix remodeling pathways. Moreover, we discuss the significant therapeutic significance of exosomal ncRNAs as PC biomarkers.
Collapse
Affiliation(s)
- Gengyu Sha
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province 225000, China.
| | - Wenjie Zhang
- School of Medicine, Chongqing University, Chongqing 400030, China.
| | - Zhengting Jiang
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province 225000, China.
| | - Qianqian Zhao
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province 225000, China.
| | - Daorong Wang
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province 225000, China; Department of General Surgery, Institute of General Surgery, Clinical Medical College, Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou 225000, China.
| | - Dong Tang
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province 225000, China; Department of General Surgery, Institute of General Surgery, Clinical Medical College, Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou 225000, China.
| |
Collapse
|
|
20
|
Ihlamur M, Kelleci K, Zengin Y, Allahverdiyev MA, Abamor EŞ. Applications of Exosome Vesicles in Different Cancer Types as Biomarkers. Curr Mol Med 2024; 24:281-297. [PMID: 36941811 DOI: 10.2174/1566524023666230320120419] [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: 07/15/2022] [Revised: 12/11/2022] [Accepted: 01/09/2023] [Indexed: 03/23/2023]
Abstract
One of the biggest challenges in the fight against cancer is early detection. Early diagnosis is vital, but there are some barriers such as economic, cultural, and personal factors. Considering the disadvantages of radiological imaging techniques or serological analysis methods used in cancer diagnosis, such as being expensive, requiring expertise, and being time-consuming, there is a need to develop faster, more reliable, and cost-effective diagnostic methods for use in cancer diagnosis. Exosomes, which are responsible for intercellular communication with sizes ranging from 30-120 nm, are naturally produced biological nanoparticles. Thanks to the cargo contents they carry, they are a potential biomarker to be used in the diagnosis of cancer. Exosomes, defined as extracellular vesicles of endosomal origin, are effective in cancer growth, progression, metastasis, and drug resistance, and changes in microenvironmental conditions during tumor development change exosome secretion. Due to their high cellular activity, tumor cells produce much higher exosomes than healthy cells. Therefore, it is known that the number of exosomes in body fluids is significantly rich compared to other cells and can act as a stand-alone diagnostic biomarker. Cancer- derived exosomes have received great attention in recent years for the early detection of cancer and the evaluation of therapeutic response. In this article, the content, properties, and differences of exosomes detected in common types of cancer (lung, liver, pancreas, ovaries, breast, colorectal), which are the leading causes of cancer-related deaths, are reviewed. We also discuss the potential utility of exosome contents as a biomarker for early detection, which is known to be important in targeted cancer therapy.
Collapse
Affiliation(s)
- Murat Ihlamur
- Yildiz Technical University, Faculty of Chemistry and Metallurgy, Department of Bioengineering, Istanbul, Turkey
- Biruni University, Vocational School, Department of Electronics and Automation, Istanbul, Turkey
| | - Kübra Kelleci
- Yildiz Technical University, Faculty of Chemistry and Metallurgy, Department of Bioengineering, Istanbul, Turkey
- Beykoz University, Vocational School, Department of Medical Services and Techniques, Istanbul, Turkey
| | - Yağmur Zengin
- Bogazici University, Biomedical Engineering Institute, Department of Biomedical Engineering, Istanbul, Turkey
| | - M Adil Allahverdiyev
- Institute of the V. Akhundov National Scientific Research Medical Prophylactic, Baku, Azerbaijan Republic
| | - Emrah Şefik Abamor
- Yildiz Technical University, Faculty of Chemistry and Metallurgy, Department of Bioengineering, Istanbul, Turkey
| |
Collapse
|
|
21
|
Valente R, Cordeiro S, Luz A, Melo MC, Rodrigues CR, Baptista PV, Fernandes AR. Doxorubicin-sensitive and -resistant colorectal cancer spheroid models: assessing tumor microenvironment features for therapeutic modulation. Front Cell Dev Biol 2023; 11:1310397. [PMID: 38188017 PMCID: PMC10771845 DOI: 10.3389/fcell.2023.1310397] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 11/27/2023] [Indexed: 01/09/2024] Open
Abstract
Introduction: The research on tumor microenvironment (TME) has recently been gaining attention due to its important role in tumor growth, progression, and response to therapy. Because of this, the development of three-dimensional cancer models that mimic the interactions in the TME and the tumor structure and complexity is of great relevance to cancer research and drug development. Methods: This study aimed to characterize colorectal cancer spheroids overtime and assess how the susceptibility or resistance to doxorubicin (Dox) or the inclusion of fibroblasts in heterotypic spheroids influence and modulate their secretory activity, namely the release of extracellular vesicles (EVs), and the response to Dox-mediated chemotherapy. Different characteristics were assessed over time, namely spheroid growth, viability, presence of hypoxia, expression of hypoxia and inflammation-associated genes and proteins. Due to the importance of EVs in biomarker discovery with impact on early diagnostics, prognostics and response to treatment, proteomic profiling of the EVs released by the different 3D spheroid models was also assessed. Response to treatment was also monitored by assessing Dox internalization and its effects on the different 3D spheroid structures and on the cell viability. Results and Discussion: The results show that distinct features are affected by both Dox resistance and the presence of fibroblasts. Fibroblasts can stabilize spheroid models, through the modulation of their growth, viability, hypoxia and inflammation levels, as well as the expressions of its associated transcripts/proteins, and promotes alterations in the protein profile exhibit by EVs. Summarily, fibroblasts can increase cell-cell and cell-extracellular matrix interactions, making the heterotypic spheroids a great model to study TME and understand TME role in chemotherapies resistance. Dox resistance induction is shown to influence the internalization of Dox, especially in homotypic spheroids, and it is also shown to influence cell viability and consequently the chemoresistance of those spheroids when exposed to Dox. Taken together these results highlight the importance of finding and characterizing different 3D models resembling more closely the in vivo interactions of tumors with their microenvironment as well as modulating drug resistance.
Collapse
Affiliation(s)
- Ruben Valente
- Associate Laboratory i4HB–Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, Caparica, Portugal
- UCIBIO–Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, Caparica, Portugal
| | - Sandra Cordeiro
- Associate Laboratory i4HB–Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, Caparica, Portugal
- UCIBIO–Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, Caparica, Portugal
| | - André Luz
- Associate Laboratory i4HB–Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, Caparica, Portugal
- UCIBIO–Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, Caparica, Portugal
| | - Maria C. Melo
- Associate Laboratory i4HB–Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, Caparica, Portugal
- UCIBIO–Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, Caparica, Portugal
| | - Catarina Roma Rodrigues
- Associate Laboratory i4HB–Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, Caparica, Portugal
- UCIBIO–Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, Caparica, Portugal
| | - Pedro V. Baptista
- Associate Laboratory i4HB–Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, Caparica, Portugal
- UCIBIO–Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, Caparica, Portugal
| | - Alexandra R. Fernandes
- Associate Laboratory i4HB–Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, Caparica, Portugal
- UCIBIO–Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, Caparica, Portugal
| |
Collapse
|
|
22
|
Qian Q, Wei Y, Xu Y, Zheng M, Wang C, Zhang S, Xie X, Ye C, Mi X. Microfluidic magnetic detection system combined with a DNA framework-mediated immune-sandwich assay for rapid and sensitive detection of tumor-derived exosomes. MICROSYSTEMS & NANOENGINEERING 2023; 9:139. [PMID: 38025882 PMCID: PMC10630345 DOI: 10.1038/s41378-023-00617-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 09/03/2023] [Accepted: 09/22/2023] [Indexed: 12/01/2023]
Abstract
Tumor-derived circulating exosomes (TDEs) are being pursued as informative and noninvasive biomarkers. However, quantitatively detecting TDEs is still challenging. Herein, we constructed a DNA tetrahedral-structured probe (TSP)-mediated microfluidic magnetic detection system (μFMS) to provide a rapid and sensitive platform for analyzing TDEs. CD63 aptamer-modified Fe3O4 magnetic nanoparticles (MNPs) were constructed to form magnetic nano-report probes (MNRs). The microfluidic chips were fabricated from glass functionalized with DNA TSP-modified aldehyde groups and a PDMS layer designed with serpentine microchannels. An induction coil-based magnetic detector was used to measure the magnetic signal. The linear dynamic range of the μFMS system for TDE assays was 1.98 × 103-1.98 × 107 particles/mL with a limit of detection of 1.98 × 103 particles/mL in PBS. There was no significant difference in TDE detection between the simulated serum and PBS, which indicated the feasibility of the constructed μFMS system for TDE analysis in complex biological systems. In terms of cost, reaction time and operation procedure, this μFMS has the potential to be developed as a clinical point-of-care testing tool for cancer diagnosis and therapeutics.
Collapse
Affiliation(s)
- Qiuling Qian
- National Key Laboratory of Materials for Integrated Circuits, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, 865 Changning Road, Shanghai, 200050 China
- Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201210 China
- University of Chinese Academy of Sciences, Beijing, 100049 China
| | - Yutong Wei
- National Key Laboratory of Materials for Integrated Circuits, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, 865 Changning Road, Shanghai, 200050 China
- University of Chinese Academy of Sciences, Beijing, 100049 China
- School of Information Science and Technology, Shanghai Tech University, Shanghai, 201210 China
| | - Yi Xu
- National Key Laboratory of Materials for Integrated Circuits, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, 865 Changning Road, Shanghai, 200050 China
- Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201210 China
| | - Mengmeng Zheng
- Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201210 China
- School of Life Sciences, Shanghai University, Shanghai, 200444 China
| | - Chenguang Wang
- Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201210 China
- University of Chinese Academy of Sciences, Beijing, 100049 China
| | - Shulin Zhang
- National Key Laboratory of Materials for Integrated Circuits, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, 865 Changning Road, Shanghai, 200050 China
| | - Xiaoming Xie
- National Key Laboratory of Materials for Integrated Circuits, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, 865 Changning Road, Shanghai, 200050 China
| | - Chaofeng Ye
- School of Information Science and Technology, Shanghai Tech University, Shanghai, 201210 China
| | - Xianqiang Mi
- National Key Laboratory of Materials for Integrated Circuits, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, 865 Changning Road, Shanghai, 200050 China
- Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201210 China
- University of Chinese Academy of Sciences, Beijing, 100049 China
- School of Physics and Optoelectronic Engineering Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, 310024 China
| |
Collapse
|
|
23
|
Fayyazpour P, Fayyazpour A, Abbasi K, Vaez-Gharamaleki Y, Zangbar MSS, Raeisi M, Mehdizadeh A. The role of exosomes in cancer biology by shedding light on their lipid contents. Pathol Res Pract 2023; 250:154813. [PMID: 37769395 DOI: 10.1016/j.prp.2023.154813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/30/2023] [Accepted: 09/08/2023] [Indexed: 09/30/2023]
Abstract
Exosomes are extracellular bilayer membrane nanovesicles released by cells after the fusion of multivesicular bodies (MVBs) with the plasma membrane. One of the interesting features of exosomes is their ability to carry and transfer various molecules, including lipids, proteins, nucleic acids, and therapeutic cargoes among cells. As intercellular signaling organelles, exosomes participate in various signaling processes such as tumor growth, metastasis, angiogenesis, epithelial-to-mesenchymal transition (EMT), and cell physiology such as cell-to-cell communication. Moreover, these particles are considered good vehicles to shuttle vaccines and drugs for therapeutic applications regarding cancers and tumor cells. These bioactive vesicles are also rich in various lipid molecules such as cholesterol, sphingomyelin (SM), glycosphingolipids, and phosphatidylserine (PS). These lipids play an important role in the formation, release, and function of the exosomes and interestingly, some lipids are used as biomarkers in cancer diagnosis. This review aimed to focus on exosomes lipid content and their role in cancer biology.
Collapse
Affiliation(s)
- Parisa Fayyazpour
- Department of Clinical Biochemistry, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ali Fayyazpour
- School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Khadijeh Abbasi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yosra Vaez-Gharamaleki
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mortaza Raeisi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mehdizadeh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
24
|
Yu H, Pan Y, Dai M, Wang X, Chen H. Mesenchymal Stem Cell-Originated Exosomal Lnc A2M-AS1 Alleviates Hypoxia/Reperfusion-Induced Apoptosis and Oxidative Stress in Cardiomyocytes. Cardiovasc Drugs Ther 2023; 37:891-904. [PMID: 35543792 DOI: 10.1007/s10557-022-07339-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/22/2022] [Indexed: 12/18/2022]
Abstract
BACKGROUND Mesenchymal stem cell (MSC)-derived exosomes play significant roles in ameliorating cardiac damage after myocardial ischemia-reperfusion (I/R) injury. Long non-coding RNA alpha-2-macroglobulin antisense RNA 1 (Lnc A2M-AS1) was found that might protect against myocardial I/R. However, whether Lnc A2M-AS1 delivery via MSC-derived exosomes could also regulate myocardial I/R injury remains unknown. METHODS Exosomes were isolated by ultracentrifugation, and qualified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. Hypoxia/reoxygenation (H/R) treatment in human cardiomyocytes was used to mimic the process of myocardial I/R in vitro. The viability and apoptosis of cardiomyocytes were detected using cell counting kit-8, flow cytometry, and Western blot assays. The contents of lactate dehydrogenase (LDH), malondialdehyde (MDA), and superoxide dismutase (SOD) were evaluated using corresponding commercial kits. The quantitative real-time polymerase chain reaction and Western blot were used to determine the expression levels of Lnc A2M-AS1, microRNA (miR)-556-5p, and X-linked inhibitor of apoptosis protein (XIAP). The binding interaction between miR-556-5p and Lnc A2M-AS1 or XIAP was confirmed by the dual-luciferase reporter, RIP and pull-down assays. RESULTS Exosomes isolated from hMSCs (hMSCs-exo) attenuated H/R-induced apoptosis and oxidative stress in cardiomyocytes. Lnc A2M-AS1 was lowly expressed in AMI patients and H/R-induced cardiomyocytes. Besides, Lnc A2M-AS1 was detectable in hMSCs-exo, exosomes derived from Lnc A2M-AS1-transfected hMSCs weakened H/R-induced apoptosis and oxidative stress, and enhanced the protective action of hMSCs-exo on H/R-induced cardiomyocytes. Further mechanism analysis showed that Lnc A2M-AS1 acted as a sponge for miR-556-5p to increase XIAP expression level. Importantly, miR-556-5p overexpression or XIAP knockdown reversed the action of exosomal Lnc A2M-AS1 on H/R-induced cardiomyocytes. CONCLUSION Lnc A2M-AS1 delivery via MSC-derived exosomes ameliorated H/R-induced cardiomyocyte apoptosis and oxidative stress via regulating miR-556-5p/XIAP, opening a new window into the pathogenesis of myocardial I/R injury.
Collapse
Affiliation(s)
- Hang Yu
- Department of Cardiovascular Surgery Intensive Care Unit, The Second Affiliated Hospital of Hainan Medical College, Haikou City, Hainan Province, China
| | - Yuxiang Pan
- Department of Critical Care Medicine, The Second Affiliated Hospital of Hainan Medical College, Haikou City, Hainan Province, China
| | - Mingming Dai
- Department of Neurology Three Areas, The Second Affiliated Hospital of Hainan Medical College, Haikou City, Hainan Province, China
| | - Xiaoqi Wang
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Hainan Medical College, No. 368 Yehai Avenue, Longhua District, Haikou City, 570105, Hainan Province, China.
| | - Haibo Chen
- Department of Blood Transfusion, The Second Affiliated Hospital of Hainan Medical College, No. 368 Yehai Avenue, Longhua District, Haikou City, 570105, Hainan Province, China.
| |
Collapse
|
|
25
|
Babar Q, Saeed A, Tabish TA, Sarwar M, Thorat ND. Targeting the tumor microenvironment: Potential strategy for cancer therapeutics. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166746. [PMID: 37160171 DOI: 10.1016/j.bbadis.2023.166746] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 04/30/2023] [Accepted: 05/02/2023] [Indexed: 05/11/2023]
Abstract
Cellular and stromal components including tumor cells, immune cells, mesenchymal cells, cancer-linked fibroblasts, and extracellular matrix, constituent tumor microenvironment (TME). TME plays a crucial role in reprogramming tumor initiation, uncontrolled proliferation, invasion and metastasis as well as response to therapeutic modalities. In recent years targeting the TME has developed as a potential strategy for treatment of cancer because of its life-threatening functions in restricting tumor development and modulating responses to standard-of-care medicines. Cold atmospheric plasma, oncolytic viral therapy, bacterial therapy, nano-vaccine, and repurposed pharmaceuticals with combination therapy, antiangiogenic drugs, and immunotherapies are among the most effective therapies directed by TME that have either been clinically authorized or are currently being studied. This article discusses above-mentioned therapies in light of targeting TME. We also cover problems related to the TME-targeted therapies, as well as future insights and practical uses in this rapidly growing field.
Collapse
Affiliation(s)
- Quratulain Babar
- Department of Biochemistry Government College University, Faisalabad, Pakistan
| | - Ayesha Saeed
- Department of Biochemistry Government College University, Faisalabad, Pakistan
| | - Tanveer A Tabish
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom
| | - Mohsin Sarwar
- Department of Biochemistry University of Management and Technology, Lahore, Pakistan
| | - Nanasaheb D Thorat
- Department of Physics, Bernal Institute, Castletroy, Limerick V94T9PX, Ireland; Nuffield Department of Women's and Reproductive Health, John Radcliffe Hospital, Medical Sciences Division, University of Oxford, Oxford OX3 9DU, United Kingdom; Limerick Digital Cancer Research Centre (LDCRC) University of Limerick, Castletroy, Limerick V94T9PX, Ireland.
| |
Collapse
|
|
26
|
Yesmin F, Furukawa K, Kambe M, Ohmi Y, Bhuiyan RH, Hasnat MA, Mizutani M, Tajima O, Hashimoto N, Tsuchida A, Kaneko K, Furukawa K. Extracellular vesicles released from ganglioside GD2-expressing melanoma cells enhance the malignant properties of GD2-negative melanomas. Sci Rep 2023; 13:4987. [PMID: 36973292 PMCID: PMC10042834 DOI: 10.1038/s41598-023-31216-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 03/08/2023] [Indexed: 03/29/2023] Open
Abstract
Exosomes (small extracellular vesicles: EVs) have attracted increasing attention from basic scientists and clinicians since they play important roles in cell-to-cell communication in various biological processes. Various features of EVs have been elucidated regarding their contents, generation and secretion mechanisms, and functions in inflammation, regeneration, and cancers. These vesicles are reported to contain proteins, RNAs, microRNAs, DNAs, and lipids. Although the roles of individual components have been rigorously studied, the presence and roles of glycans in EVs have rarely been reported. In particular, glycosphingolipids in EVs have not been investigated to date. In this study, the expression and function of a representative cancer-associated ganglioside, GD2, in malignant melanomas was investigated. Generally, cancer-associated gangliosides have been shown to enhance malignant properties and signals in cancers. Notably, EVs derived from GD2-expressing melanomas enhanced the malignant phenotypes of GD2-negative melanomas, such as cell growth, invasion, and cell adhesion, in a dose-dependent manner. The EVs also induced increased phosphorylation of signaling molecules such as EGF receptor and focal adhesion kinase. These results suggest that EVs released from cancer-associated ganglioside-expressing cells exert many functions that have been reported as a function of these gangliosides and regulate microenvironments, including total aggravation of heterogeneous cancer tissues, leading to more malignant and advanced cancer types.
Collapse
Affiliation(s)
- Farhana Yesmin
- Department of Biomedical Sciences, Chubu University College of Life and Health Sciences, Matsumoto 1200, Kasugai, Aichi, 487-8501, Japan
| | - Keiko Furukawa
- Department of Biomedical Sciences, Chubu University College of Life and Health Sciences, Matsumoto 1200, Kasugai, Aichi, 487-8501, Japan
| | - Mariko Kambe
- Department of Biomedical Sciences, Chubu University College of Life and Health Sciences, Matsumoto 1200, Kasugai, Aichi, 487-8501, Japan
| | - Yuhsuke Ohmi
- Department of Clinical Engineering, Chubu University College of Life and Health Sciences, Matsumoto 1200, Kasugai, Aichi, 487-8501, Japan
| | - Robiul Hasan Bhuiyan
- Department of Biomedical Sciences, Chubu University College of Life and Health Sciences, Matsumoto 1200, Kasugai, Aichi, 487-8501, Japan
- Department of Biochemistry and Molecular Biology, University of Chittagong, 4331, Chittagong, Bangladesh
| | - Mohammad Abul Hasnat
- Department of Biomedical Sciences, Chubu University College of Life and Health Sciences, Matsumoto 1200, Kasugai, Aichi, 487-8501, Japan
| | - Momoka Mizutani
- Department of Biomedical Sciences, Chubu University College of Life and Health Sciences, Matsumoto 1200, Kasugai, Aichi, 487-8501, Japan
| | - Orie Tajima
- Department of Biomedical Sciences, Chubu University College of Life and Health Sciences, Matsumoto 1200, Kasugai, Aichi, 487-8501, Japan
| | - Noboru Hashimoto
- Department of Tissue Regeneration, Tokushima University School of Dentistry, Kuramoto-Cho 3, Tokushima, 770-8504, Japan
| | - Akiko Tsuchida
- Laboratory of Glyco- Bioengineering, The Noguchi Institute, Itabashi, 173-0003, Japan
| | - Kei Kaneko
- Department of Biomedical Sciences, Chubu University College of Life and Health Sciences, Matsumoto 1200, Kasugai, Aichi, 487-8501, Japan
| | - Koichi Furukawa
- Department of Biomedical Sciences, Chubu University College of Life and Health Sciences, Matsumoto 1200, Kasugai, Aichi, 487-8501, Japan.
| |
Collapse
|
|
27
|
Conditioned Medium - Is it an Undervalued Lab Waste with the Potential for Osteoarthritis Management? Stem Cell Rev Rep 2023:10.1007/s12015-023-10517-1. [PMID: 36790694 PMCID: PMC10366316 DOI: 10.1007/s12015-023-10517-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2023] [Indexed: 02/16/2023]
Abstract
BACKGROUND The approaches currently used in osteoarthritis (OA) are mainly short-term solutions with unsatisfactory outcomes. Cell-based therapies are still controversial (in terms of the sources of cells and the results) and require strict culture protocol, quality control, and may have side-effects. A distinct population of stromal cells has an interesting secretome composition that is underrated and commonly ends up as biological waste. Their unique properties could be used to improve the existing techniques due to protective and anti-ageing properties. SCOPE OF REVIEW In this review, we seek to outline the advantages of the use of conditioned media (CM) and exosomes, which render them superior to other cell-based methods, and to summarise current information on the composition of CM and their effect on chondrocytes. MAJOR CONCLUSIONS CM are obtainable from a variety of mesenchymal stromal cell (MSC) sources, such as adipose tissue, bone marrow and umbilical cord, which is significant to their composition. The components present in CMs include proteins, cytokines, growth factors, chemokines, lipids and ncRNA with a variety of functions. In most in vitro and in vivo studies CM from MSCs had a beneficial effect in enhance processes associated with chondrocyte OA pathomechanism. GENERAL SIGNIFICANCE This review summarises the information available in the literature on the function of components most commonly detected in MSC-conditioned media, as well as the effect of CM on OA chondrocytes in in vitro culture. It also highlights the need to standardise protocols for obtaining CM, and to conduct clinical trials to transfer the effects obtained in vitro to human subjects.
Collapse
|
|
28
|
Liu C, Ren C, Guo L, Yang C, Yu Q. Exosome-mediated circTTLL5 transfer promotes hepatocellular carcinoma malignant progression through miR-136-5p/KIAA1522 axis. Pathol Res Pract 2023; 241:154276. [PMID: 36528986 DOI: 10.1016/j.prp.2022.154276] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 12/07/2022] [Accepted: 12/09/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Exosomes have been recognized as messengers for intercellular communication in tumor microenvironment. Exosomal circRNAs are reported to be important in tumors. Here, this study identified the potential function of exosomal circular RNA tubulin tyrosine ligase like 5 (circTTLL5) in hepatocellular carcinoma (HCC) progression. METHODS The expression of circTTLL5, microRNA (miR)- 136-5p and KIAA1522 was detected using qRT-PCR and Western blot assays. Exosomes were isolated by ultracentrifugation, and qualified by transmission electron microscopy (TEM) and Western blot. Cell proliferation, apoptosis and metastasis were investigated using cell counting kit-8, colony formation, flow cytometry, would healing, transwell and Western blot assays, respectively. The interaction between miR-136-5p and circTTLL5 or KIAA1522 was confirmed by dual-luciferase reporter and pull-down assays. In vivo experiment was performed using Xenograft models. RESULTS CircTTLL5 was incorporated into exosomes and highly expressed in HCC tissues and cells. CircTTLL5 knockdown suppressed HCC cell proliferation and metastasis in vitro and impeded tumor growth in mice. CircTTLL5 could be delivered to recipient cells via exosomes, and treatment of circTTLL5-elevated exosomes could attenuate the anticancer effects of circTTLL5 knockdown on HCC in vitro and in vivo. Mechanically, circTTLL5 could sponge miR-136-5p, which controlled its down-stream target KIAA1522. MiR-136-5p inhibition reversed the effects of circTTLL5 knockdown on HCC cells. Besides that, miR-136-5p re-expression inhibited HCC cell growth and metastasis, which was abated by KIAA1522 overexpression. CONCLUSION Exosomal circTTLL5 promoted HCC progression through miR-136-5p/KIAA1522 axis, suggesting that blockage of the exosome-mediated transfer of circTTLL5 might be a therapeutic target for HCC.
Collapse
Affiliation(s)
- Chanjuan Liu
- Clinical Laboratory, the Second Affiliated Hospital of Mudanjiang Medical College, China
| | - Chunna Ren
- Clinical Laboratory, the Second Affiliated Hospital of Mudanjiang Medical College, China
| | - Ling Guo
- Personnel Section, the Second Affiliated Hospital of Mudanjiang Medical College, China
| | - Cuizhen Yang
- Clinical Laboratory, the Second Affiliated Hospital of Mudanjiang Medical College, China
| | - Qi Yu
- Clinical Laboratory, the Second Affiliated Hospital of Mudanjiang Medical College, China.
| |
Collapse
|
|
29
|
Sarcar B, Fang B, Izumi V, O Nunez Lopez Y, Tassielli A, Pratley R, Jeong D, Permuth JB, Koomen JM, Fleming JB, Stewart PA. A comparative Proteomics Analysis Identified Differentially Expressed Proteins in Pancreatic Cancer-Associated Stellate Cell Small Extracellular Vesicles. Mol Cell Proteomics 2022; 21:100438. [PMID: 36332889 PMCID: PMC9792568 DOI: 10.1016/j.mcpro.2022.100438] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 10/03/2022] [Accepted: 10/31/2022] [Indexed: 11/09/2022] Open
Abstract
Human pancreatic stellate cells (HPSCs) are an essential stromal component and mediators of pancreatic ductal adenocarcinoma (PDAC) progression. Small extracellular vesicles (sEVs) are membrane-enclosed nanoparticles involved in cell-to-cell communications and are released from stromal cells within PDAC. A detailed comparison of sEVs from normal pancreatic stellate cells (HPaStec) and from PDAC-associated stellate cells (HPSCs) remains a gap in our current knowledge regarding stellate cells and PDAC. We hypothesized there would be differences in sEVs secretion and protein expression that might contribute to PDAC biology. To test this hypothesis, we isolated sEVs using ultracentrifugation followed by characterization by electron microscopy and Nanoparticle Tracking Analysis. We report here our initial observations. First, HPSC cells derived from PDAC tumors secrete a higher volume of sEVs when compared to normal pancreatic stellate cells (HPaStec). Although our data revealed that both normal and tumor-derived sEVs demonstrated no significant biological effect on cancer cells, we observed efficient uptake of sEVs by both normal and cancer epithelial cells. Additionally, intact membrane-associated proteins on sEVs were essential for efficient uptake. We then compared sEV proteins isolated from HPSCs and HPaStecs cells using liquid chromatography-tandem mass spectrometry. Most of the 1481 protein groups identified were shared with the exosome database, ExoCarta. Eighty-seven protein groups were differentially expressed (selected by 2-fold difference and adjusted p value ≤0.05) between HPSC and HPaStec sEVs. Of note, HPSC sEVs contained dramatically more CSE1L (chromosome segregation 1-like protein), a described marker of poor prognosis in patients with pancreatic cancer. Based on our results, we have demonstrated unique populations of sEVs originating from stromal cells with PDAC and suggest that these are significant to cancer biology. Further studies should be undertaken to gain a deeper understanding that could drive novel therapy.
Collapse
Affiliation(s)
- Bhaswati Sarcar
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Bin Fang
- Proteomics and Metabolomics Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Victoria Izumi
- Proteomics and Metabolomics Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | | | - Alexandra Tassielli
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Richard Pratley
- Translational Research Institute, Advent Health, Orlando, Florida, USA
| | - Daniel Jeong
- Department of Diagnostic and Interventional Radiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Jennifer B Permuth
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA; Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - John M Koomen
- Proteomics and Metabolomics Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Jason B Fleming
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
| | - Paul A Stewart
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
| |
Collapse
|
|
30
|
Xie J, Jiang H, Zhao Y, Jin XR, Li B, Zhu Z, Zhang L, Liu J. Prognostic and diagnostic value of circRNA expression in prostate cancer: A systematic review and meta-analysis. Front Oncol 2022; 12:945143. [PMID: 36419885 PMCID: PMC9676972 DOI: 10.3389/fonc.2022.945143] [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: 05/31/2022] [Accepted: 10/10/2022] [Indexed: 03/11/2024] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) are receiving increasing attention as novel biomarkers. Our goal was to investigate the diagnostic, clinicopathological, and prognostic utility of circRNAs in prostate cancer (PCa). METHODS Relevant literature was searched in PubMed, Web of Science, and EMBASE. Sensitivity, specificity, diagnostic odds ratio (DOR), negative likelihood ratio (NLR), positive likelihood ratio (PLR), and the area under the curve (AUC) were calculated to evaluate the diagnostic accuracy of circRNA expression. circRNAs' clinical, pathological, and prognostic value was examined using pooled odds ratios (ORs) and hazard ratios (HRs). RESULTS This meta-analysis included 23 studies, with 5 for diagnosis, 16 for clinicopathological parameters, and 10 for prognosis. For diagnostic value, the pooled sensitivity, pooled specificity, PLR, NLR, DOR, and AUC were 0.82, 0.62, 2.17, 0.29, 7.37, and 0.81, respectively. Upregulation of carcinogenic circRNAs was associated with poor clinical parameters (Gleason score: OR = 0.222, 95% CI: 0.145-0.340; T classification: OR = 0.274, 95% CI: 0.175-0.430; lymph node metastasis: OR = 0.353, 95% CI: 0.175-0.716; tumor size: OR = 0.226, 95% CI: 0.099-0.518) and could predict poor survival outcomes (HR = 2.408, 95% CI: 1.559-3.720, p < 0.001). Conversely, downregulation of tumor-suppressor circRNAs was also associated with poor clinical parameters (Gleason score: OR = 1.689, 95% CI: 1.144-2.493; T classification: OR = 2.586, 95% CI: 1.779-3.762) and worse prognosis (HR = 1.739, 95% CI: 1.147-2.576, p = 0.006). CONCLUSION Our results showed that circRNAs might be useful biomarkers for the diagnosis and prognosis of PCa. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/prospero/, identifier CRD42021284785.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Jinbo Liu
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| |
Collapse
|
|
31
|
Hadizadeh N, Bagheri D, Shamsara M, Hamblin MR, Farmany A, Xu M, Liang Z, Razi F, Hashemi E. Extracellular vesicles biogenesis, isolation, manipulation and genetic engineering for potential in vitro and in vivo therapeutics: An overview. Front Bioeng Biotechnol 2022; 10:1019821. [PMID: 36406206 PMCID: PMC9672340 DOI: 10.3389/fbioe.2022.1019821] [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: 08/15/2022] [Accepted: 10/18/2022] [Indexed: 08/16/2023] Open
Abstract
The main goals of medicine consist of early detection and effective treatment of different diseases. In this regard, the rise of exosomes as carriers of natural biomarkers has recently attracted a lot of attention and managed to shed more light on the future of early disease diagnosis methods. Here, exosome biogenesis, its role as a biomarker in metabolic disorders, and recent advances in state-of-art technologies for exosome detection and isolation will be reviewed along with future research directions and challenges regarding the manipulation and genetic engineering of exosomes for potential in vitro and in vivo disease diagnosis approaches.
Collapse
Affiliation(s)
- Nastaran Hadizadeh
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Diba Bagheri
- Department of Molecular Genetics, Tarbiat Modares University, Tehran, Iran
| | - Mehdi Shamsara
- Department of Animal Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Michael R. Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Abbas Farmany
- Dental Research Centre and Dental Implant Research Centre, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mengdi Xu
- Shenzhen Bay Laboratory, Institute of Molecular Physiology, Shenzhen, China
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Zhuobin Liang
- Shenzhen Bay Laboratory, Institute of Molecular Physiology, Shenzhen, China
| | - Farideh Razi
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular—Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ehsan Hashemi
- Department of Animal Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
- Shenzhen Bay Laboratory, Institute of Molecular Physiology, Shenzhen, China
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular—Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
32
|
Mesenchymal Stem Cell-Derived Extracellular Vesicles Therapy for Pulmonary Hypertension: A Comprehensive Review of Preclinical Studies. J Interv Cardiol 2022; 2022:5451947. [PMID: 36419957 PMCID: PMC9652076 DOI: 10.1155/2022/5451947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 10/09/2022] [Accepted: 10/20/2022] [Indexed: 11/06/2022] Open
Abstract
Pulmonary hypertension (PH) is a type of clinical pathophysiological syndrome characterized by a progressive increase in pulmonary vascular resistance and subsequent progressive failure of the right heart function, and is a common complication of many diseases. Mesenchymal stem cells (MSCs) autonomously home to sites damaged by disease, repair damaged tissues, and participate in the regulation of systemic inflammation and immune responses, which have good clinical application prospects. Extracellular vesicles (EVs), such as exosomes and microvesicles, participate in various biological activities by regulating intercellular communication. Exosomes secreted into the extracellular environment also affect the host immune system. MSC-derived extracellular vesicles (MSC-EVs), as a mediator in the paracrine processes of MSCs, carry biologically active substances such as proteins, lipids, mRNA, and micro-RNA. MSC-EVs therapies, safer than cell-based treatments, have been shown to be effective in modulating macrophages to support anti-inflammatory phenotypes, which are strongly related to histological and functional benefits in preclinical models of pulmonary hypertension. The main effects of active substances and their potential medical value have attracted wide attention from researchers. This article reviews the role and relevant mechanisms of MSC-EVs in the treatment of pulmonary hypertension in recent studies and provides a basis for their future clinical applications.
Collapse
|
|
33
|
Focus on organoids: cooperation and interconnection with extracellular vesicles - Is this the future of in vitro modeling? Semin Cancer Biol 2022; 86:367-381. [PMID: 34896267 DOI: 10.1016/j.semcancer.2021.12.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/29/2021] [Accepted: 12/07/2021] [Indexed: 01/27/2023]
Abstract
Organoids are simplified in vitro model systems of organs that are used for modeling tissue development and disease, drug screening, cell therapy, and personalized medicine. Despite considerable success in the design of organoids, challenges remain in achieving real-life applications. Organoids serve as unique and organized groups of micro physiological systems that are capable of self-renewal and self-organization. Moreover, they exhibit similar organ functionality(ies) as that of tissue(s) of origin. Organoids can be designed from adult stem cells, induced pluripotent stem cells, or embryonic stem cells. They consist of most of the important cell types of the desired tissue/organ along with the topology and cell-cell interactions that are highly similar to those of an in vivo tissue/organ. Organoids have gained interest in human biomedical research, as they demonstrate high promise for use in basic, translational, and applied research. As in vitro models, organoids offer significant opportunities for reducing the reliance and use of experimental animals. In this review, we will provide an overview of organoids, as well as those intercellular communications mediated by extracellular vesicles (EVs), and discuss the importance of organoids in modeling a tumor immune microenvironment (TIME). Organoids can also be exploited to develop a better understanding of intercellular communications mediated by EVs. Also, organoids are useful in mimicking TIME, thereby offering a better-controlled environment for studying various associated biological processes and immune cell types involved in tumor immunity, such as T-cells, macrophages, dendritic cells, and myeloid-derived suppressor cells, among others.
Collapse
|
|
34
|
He B, Huang Z, Huang C, Nice EC. Clinical applications of plasma proteomics and peptidomics: Towards precision medicine. Proteomics Clin Appl 2022; 16:e2100097. [PMID: 35490333 DOI: 10.1002/prca.202100097] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 04/16/2022] [Accepted: 04/28/2022] [Indexed: 02/05/2023]
Abstract
In the context of precision medicine, disease treatment requires individualized strategies based on the underlying molecular characteristics to overcome therapeutic challenges posed by heterogeneity. For this purpose, it is essential to develop new biomarkers to diagnose, stratify, or possibly prevent diseases. Plasma is an available source of biomarkers that greatly reflects the physiological and pathological conditions of the body. An increasing number of studies are focusing on proteins and peptides, including many involving the Human Proteome Project (HPP) of the Human Proteome Organization (HUPO), and proteomics and peptidomics techniques are emerging as critical tools for developing novel precision medicine preventative measures. Excitingly, the emerging plasma proteomics and peptidomics toolbox exhibits a huge potential for studying pathogenesis of diseases (e.g., COVID-19 and cancer), identifying valuable biomarkers and improving clinical management. However, the enormous complexity and wide dynamic range of plasma proteins makes plasma proteome profiling challenging. Herein, we summarize the recent advances in plasma proteomics and peptidomics with a focus on their emerging roles in COVID-19 and cancer research, aiming to emphasize the significance of plasma proteomics and peptidomics in clinical applications and precision medicine.
Collapse
Affiliation(s)
- Bo He
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, P. R. China
| | - Zhao Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, P. R. China
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, P. R. China.,Department of Pharmacology, and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang, China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| |
Collapse
|
|
35
|
Heestermans R, De Brouwer W, Maes K, Vande Broek I, Vaeyens F, Olsen C, Caljon B, De Becker A, Bakkus M, Schots R, Van Riet I. Liquid Biopsy-Derived DNA Sources as Tools for Comprehensive Mutation Profiling in Multiple Myeloma: A Comparative Study. Cancers (Basel) 2022; 14:cancers14194901. [PMID: 36230824 PMCID: PMC9563447 DOI: 10.3390/cancers14194901] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/04/2022] [Accepted: 10/05/2022] [Indexed: 11/28/2022] Open
Abstract
Simple Summary Multiple myeloma (MM) is characterized by an expansion of plasma cells in the bone marrow (BM). The genetics of MM are highly complex with multiple mutations and genetic subpopulations of tumor cells that arise during the disease evolution, affecting prognosis and treatment response. Standard bone marrow DNA analysis requires an invasive sample collection and does not always reflect the complete mutation profile. Therefore, we examined the possibility to use peripheral blood-based liquid biopsies as an alternative DNA source for mutation profiling. By comparing DNA from circulating tumor cells with circulating tumor-derived vesicles and cell-free DNA (cfDNA), we found that the latter provided the best concordance with bone marrow DNA and also showed mutations derived from myeloma cell populations that were undetectable in bone marrow. Our comparative study indicates that cfDNA is the preferable circulating biomarker for genetic characterization in MM and can provide additional information compared to standard BM analysis. Abstract The analysis of bone marrow (BM) samples in multiple myeloma (MM) patients can lead to the underestimation of the genetic heterogeneity within the tumor. Blood-derived liquid biopsies may provide a more comprehensive approach to genetic characterization. However, no thorough comparison between the currently available circulating biomarkers as tools for mutation profiling in MM has been published yet and the use of extracellular vesicle-derived DNA for this purpose in MM has not yet been investigated. Therefore, we collected BM aspirates and blood samples in 30 patients with active MM to isolate five different DNA types, i.e., cfDNA, EV-DNA, BM-DNA and DNA isolated from peripheral blood mononucleated cells (PBMNCs-DNA) and circulating tumor cells (CTC-DNA). DNA was analyzed for genetic variants with targeted gene sequencing using a 165-gene panel. After data filtering, 87 somatic and 39 germline variants were detected among the 149 DNA samples used for sequencing. cfDNA showed the highest concordance with the mutation profile observed in BM-DNA and outperformed EV-DNA, CTC-DNA and PBMNCs-DNA. Of note, 16% of all the somatic variants were only detectable in circulating biomarkers. Based on our analysis, cfDNA is the preferable circulating biomarker for genetic characterization in MM and its combined use with BM-DNA allows for comprehensive mutation profiling in MM.
Collapse
Affiliation(s)
- Robbe Heestermans
- Department of Clinical Biology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium
- Department of Hematology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium
- Research Group Hematology and Immunology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Wouter De Brouwer
- Department of Hematology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium
- Research Group Hematology and Immunology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Ken Maes
- Clinical Sciences, Research Group Reproduction and Genetics, Centre for Medical Genetics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium
| | - Isabelle Vande Broek
- Department of Oncology and Hematology, VITAZ, Moerlandstraat 1, 9100 Sint-Niklaas, Belgium
| | - Freya Vaeyens
- Clinical Sciences, Research Group Reproduction and Genetics, Centre for Medical Genetics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium
| | - Catharina Olsen
- Clinical Sciences, Research Group Reproduction and Genetics, Centre for Medical Genetics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium
- Brussels Interuniversity Genomics High Throughput Core (BRIGHTcore), Vrije Universiteit Brussel (VUB), Université Libre de Bruxelles (ULB), Laarbeeklaan 101, 1090 Brussels, Belgium
| | - Ben Caljon
- Brussels Interuniversity Genomics High Throughput Core (BRIGHTcore), Vrije Universiteit Brussel (VUB), Université Libre de Bruxelles (ULB), Laarbeeklaan 101, 1090 Brussels, Belgium
| | - Ann De Becker
- Department of Hematology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium
- Research Group Hematology and Immunology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Marleen Bakkus
- Department of Clinical Biology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium
- Research Group Hematology and Immunology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Rik Schots
- Department of Hematology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium
- Research Group Hematology and Immunology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Ivan Van Riet
- Department of Hematology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium
- Research Group Hematology and Immunology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
- Correspondence:
| |
Collapse
|
|
36
|
Jin Y, Xing J, Xu K, Liu D, Zhuo Y. Exosomes in the tumor microenvironment: Promoting cancer progression. Front Immunol 2022; 13:1025218. [PMID: 36275738 PMCID: PMC9584056 DOI: 10.3389/fimmu.2022.1025218] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Exosomes, which are extracellular vesicles produced by endosomes, are important performers of intercellular communication functions. For more than three decades, there has been a growing awareness of exosomes as the contents of the tumor microenvironment and their intimate connection to the development of cancer. The composition, generation, and uptake of exosomes as well as their roles in tumor metastasis, angiogenesis, and immunosuppression are discussed in this paper. In order to stop the progression of cancer, it is crucial to find new diagnostic biomarkers and therapeutic targets for the disease. Knowing the biological characteristics of exosomes and their functions in tumor development helps in this endeavor.
Collapse
Affiliation(s)
- Ye Jin
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Jianming Xing
- School of Life Sciences, Jilin University, Changchun, China
| | - Kejin Xu
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Da Liu
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
- School of Acupuncture-Moxi Bustion and Tuina, Changchun University of Chinese Medicine, Changchun, China
- *Correspondence: Da Liu, ; Yue Zhuo,
| | - Yue Zhuo
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
- School of Acupuncture-Moxi Bustion and Tuina, Changchun University of Chinese Medicine, Changchun, China
- *Correspondence: Da Liu, ; Yue Zhuo,
| |
Collapse
|
|
37
|
Targeted inhibition of tumor-derived exosomes as a novel therapeutic option for cancer. Exp Mol Med 2022; 54:1379-1389. [PMID: 36117219 PMCID: PMC9534887 DOI: 10.1038/s12276-022-00856-3] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 07/07/2022] [Accepted: 07/21/2022] [Indexed: 11/25/2022] Open
Abstract
Mounting evidence indicates that tumor-derived exosomes (TDEs) play critical roles in tumor development and progression by regulating components in the tumor microenvironment (TME) in an autocrine or paracrine manner. Moreover, due to their delivery of critical molecules that react to chemotherapy and immunotherapy, TDEs also contribute to tumor drug resistance and impede the effective response of antitumor immunotherapy, thereby leading to poor clinical outcomes. There is a pressing need for the inhibition or removal of TDEs to facilitate the treatment and prognosis of cancer patients. Here, in the present review, we systematically overviewed the current strategies for TDE inhibition and clearance, providing novel insights for future tumor interventions in translational medicine. Moreover, existing challenges and potential prospects for TDE-targeted cancer therapy are also discussed to bridge the gaps between progress and promising applications. Inhibiting or removing tumor-derived exosomes (TDEs), tiny membrane-bound packets of DNA, RNA, and proteins secreted by tumors, may improve cancer therapies. TDEs can suppress the body’s immune response, promote tumor progression and spread, and reduce efficacy of cancer drugs and immunotherapy. Gang Chen at Wuhan University, China, and co-workers have reviewed ways to remove or inhibit production of TDEs. They report that disruption of the genes for production of TDEs, drugs that inhibit TDE secretion, and removal of TDEs via plasma exchange or dialysis are all being investigated and show promise for reducing patient TDE load, thereby increasing the efficacy of anti-cancer drugs and immunotherapy. Future challenges include reducing side effects and finding less invasive ways to filter out TDEs. Gaining a better understanding of TDEs may help to improve therapies for many types of cancer.
Collapse
|
|
38
|
Karami Fath M, Azami J, Masoudi A, Mosaddeghi Heris R, Rahmani E, Alavi F, Alagheband Bahrami A, Payandeh Z, Khalesi B, Dadkhah M, Pourzardosht N, Tarhriz V. Exosome-based strategies for diagnosis and therapy of glioma cancer. Cancer Cell Int 2022; 22:262. [PMID: 35989351 PMCID: PMC9394011 DOI: 10.1186/s12935-022-02642-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 06/26/2022] [Indexed: 11/10/2022] Open
Abstract
Glioblastoma belongs to the most aggressive type of cancer with a low survival rate that is characterized by the ability in forming a highly immunosuppressive tumor microenvironment. Intercellular communication are created via exosomes in the tumor microenvironment through the transport of various biomolecules. They are primarily involved in tumor growth, differentiation, metastasis, and chemotherapy or radiation resistance. Recently several studies have highlighted the critical role of tumor-derived exosomes against immune cells. According to the structural and functional properties, exosomes could be essential instruments to gain a better molecular mechanism for tumor understanding. Additionally, they are qualified as diagnostic/prognostic markers and therapeutic tools for specific targeting of invasive tumor cells such as glioblastomas. Due to the strong dependency of exosome features on the original cells and their developmental status, it is essential to review their critical modulating molecules, clinical relevance to glioma, and associated signaling pathways. This review is a non-clinical study, as the possible role of exosomes and exosomal microRNAs in glioma cancer are reported. In addition, their content to overcome cancer resistance and their potential as diagnostic biomarkers are analyzed.
Collapse
Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Jalil Azami
- Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | - Alireza Masoudi
- Department of Laboratory Sciences, Faculty of Alied Medical Sciences, Qom University of Medical Sciences, Qom, Iran
| | | | - Elnaz Rahmani
- Department of Clinical Pharmacy, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| | - Fatemeh Alavi
- Department of Pathobiology, Faculty of Specialized Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Armina Alagheband Bahrami
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Payandeh
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden
| | - Bahman Khalesi
- Department of Research and Production of Poultry Viral Vaccine, Razi Vaccine and Serum Research, Tabriz, Iran
| | - Masoomeh Dadkhah
- Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Navid Pourzardosht
- Biochemistry Department, Guilan University of Medical Sciences, Rasht, Iran
| | - Vahideh Tarhriz
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
39
|
Shefer A, Yalovaya A, Tamkovich S. Exosomes in Breast Cancer: Involvement in Tumor Dissemination and Prospects for Liquid Biopsy. Int J Mol Sci 2022; 23:8845. [PMID: 36012109 PMCID: PMC9408748 DOI: 10.3390/ijms23168845] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/04/2022] [Accepted: 08/06/2022] [Indexed: 12/03/2022] Open
Abstract
In women, breast cancer (BC) is the most commonly diagnosed cancer (24.5%) and the leading cause of cancer death (15.5%). Understanding how this heterogeneous disease develops and the confirm mechanisms behind tumor progression is of utmost importance. Exosomes are long-range message vesicles that mediate communication between cells in physiological conditions but also in pathology, such as breast cancer. In recent years, there has been an exponential rise in the scientific studies reporting the change in morphology and cargo of tumor-derived exosomes. Due to the transfer of biologically active molecules, such as RNA (microRNA, long non-coding RNA, mRNA, etc.) and proteins (transcription factors, enzymes, etc.) into recipient cells, these lipid bilayer 30-150 nm vesicles activate numerous signaling pathways that promote tumor development. In this review, we attempt to shed light on exosomes' involvement in breast cancer pathogenesis (including epithelial-to-mesenchymal transition (EMT), tumor cell proliferation and motility, metastatic processes, angiogenesis stimulation, and immune system repression). Moreover, the potential use of exosomes as promising diagnostic biomarkers for liquid biopsy of breast cancer is also discussed.
Collapse
Affiliation(s)
- Aleksei Shefer
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia
- V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, 630090 Novosibirsk, Russia
| | - Alena Yalovaya
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - Svetlana Tamkovich
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia
- V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, 630090 Novosibirsk, Russia
| |
Collapse
|
|
40
|
Annexin A5 as a targeting agent for cancer treatment. Cancer Lett 2022; 547:215857. [DOI: 10.1016/j.canlet.2022.215857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 07/29/2022] [Accepted: 08/01/2022] [Indexed: 11/19/2022]
|
|
41
|
Ahmad E, Ali A, Nimisha, Kumar Sharma A, Apurva, Kumar A, Dar GM, Sumayya Abdul Sattar R, Verma R, Mahajan B, Singh Saluja S. Molecular markers in cancer. Clin Chim Acta 2022; 532:95-114. [DOI: https:/doi.org/10.1016/j.cca.2022.05.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/28/2023]
|
|
42
|
Huang Y, Kanada M, Ye J, Deng Y, He Q, Lei Z, Chen Y, Li Y, Qin P, Zhang J, Wei J. Exosome-mediated remodeling of the tumor microenvironment: From local to distant intercellular communication. Cancer Lett 2022; 543:215796. [PMID: 35728740 DOI: 10.1016/j.canlet.2022.215796] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/31/2022] [Accepted: 06/15/2022] [Indexed: 11/29/2022]
Abstract
Extracellular vesicles (EVs) are membrane-enveloped nanoscale particles that carry various bioactive signaling molecules secreted by cells. Their biological roles depend on the original cell type from which they are derived and their inclusions. Exosomes, a class of EVs, are released by almost all eukaryotic cell types, including tumor cells. Tumor cell-derived exosomes mediate signal transduction between tumor cells and surrounding non-tumor cells. This intercellular communication actively contributes to the remodeling of the tumor microenvironment (TME) to enable tumor growth, invasion, and metastasis. This review summarizes the latest progress in the exploration of exosome-mediated cell-cell communication implicated in TME remodeling and underlying mechanisms. We focus on the role of cell-cell interactions mediated by tumor cell-derived exosomes in promoting invasion and metastasis, and their potential as a therapeutic intervention target against distant metastasis. We also discuss the clinical translational significance of tumor-derived exosomes for early diagnosis, efficacy and progression evaluations.
Collapse
Affiliation(s)
- Yujuan Huang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, China
| | - Masamitsu Kanada
- Department of Pharmacology & Toxicology, Institute for Quantitative Health Science and Engineering (IQ), Michigan State University, East Lansing, MI, 48824, USA
| | - Jiaxiang Ye
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, China
| | - Yayan Deng
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, China
| | - Qian He
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China
| | - Zhengyang Lei
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China
| | - Yong Chen
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, China
| | - Yongqiang Li
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, China
| | - Peiwu Qin
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China
| | - Jinyan Zhang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, China.
| | - Jiazhang Wei
- Department of Otolaryngology & Head and Neck, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 6 Taoyuan Road, Nanning, 530021, China.
| |
Collapse
|
|
43
|
Ahmad E, Ali A, Nimisha, Kumar Sharma A, Apurva, Kumar A, Mehdi G, Sumayya Abdul Sattar R, Verma R, Mahajan B, Singh Saluja S. Molecular markers in cancer. Clin Chim Acta 2022; 532:95-114. [DOI: 10.1016/j.cca.2022.05.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 05/31/2022] [Accepted: 05/31/2022] [Indexed: 12/01/2022]
|
|
44
|
Moslehi M, Moazamiyanfar R, Dakkali MS, Rezaei S, Rastegar-Pouyani N, Jafarzadeh E, Mouludi K, Khodamoradi E, Taeb S, Najafi M. Modulation of the immune system by melatonin; implications for cancer therapy. Int Immunopharmacol 2022; 108:108890. [PMID: 35623297 DOI: 10.1016/j.intimp.2022.108890] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/07/2022] [Accepted: 05/19/2022] [Indexed: 12/12/2022]
Abstract
Immune system interactions within the tumour have a key role in the resistance or sensitization of cancer cells to anti-cancer agents. On the other hand, activation of the immune system in normal tissues following chemotherapy or radiotherapy is associated with acute and late effects such as inflammation and fibrosis. Some immune responses can reduce the efficiency of anti-cancer therapy and also promote normal tissue toxicity. Modulation of immune responses can boost the efficiency of anti-tumour therapy and alleviate normal tissue toxicity. Melatonin is a natural body agent that has shown promising results for modulating tumour response to therapy and also alleviating normal tissue toxicity. This review tries to focus on the immunomodulatory actions of melatonin in both tumour and normal tissues. We will explain how anti-cancer drugs may cause toxicity for normal tissues and how tumours can adapt themselves to ionizing radiation and anti-cancer drugs. Then, cellular and molecular mechanisms of immunoregulatory effects of melatonin alone or combined with other anti-cancer agents will be discussed.
Collapse
Affiliation(s)
- Masoud Moslehi
- Department of Medical Physics, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Reza Moazamiyanfar
- Department of Medical Nanotechnology, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Sepideh Rezaei
- Department of Chemistry, University of Houston, 3585 Cullen Blvd., Fleming Bldg. Rm 112, Houston, TX 77204-5003, USA
| | - Nima Rastegar-Pouyani
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Emad Jafarzadeh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Kave Mouludi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ehsan Khodamoradi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Shahram Taeb
- Department of Radiology, School of Paramedical Sciences, Guilan University of Medical Sciences, Rasht, Iran; Medical Biotechnology Research Center, School of Paramedical Sciences, Guilan University of Medical Sciences, Rasht, Iran
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran; Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| |
Collapse
|
|
45
|
Ginini L, Billan S, Fridman E, Gil Z. Insight into Extracellular Vesicle-Cell Communication: From Cell Recognition to Intracellular Fate. Cells 2022; 11:1375. [PMID: 35563681 PMCID: PMC9101098 DOI: 10.3390/cells11091375] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 04/13/2022] [Accepted: 04/14/2022] [Indexed: 01/27/2023] Open
Abstract
Extracellular vesicles (EVs) are heterogamous lipid bilayer-enclosed membranous structures secreted by cells. They are comprised of apoptotic bodies, microvesicles, and exosomes, and carry a range of nucleic acids and proteins that are necessary for cell-to-cell communication via interaction on the cells surface. They initiate intracellular signaling pathways or the transference of cargo molecules, which elicit pleiotropic responses in recipient cells in physiological processes, as well as pathological processes, such as cancer. It is therefore important to understand the molecular means by which EVs are taken up into cells. Accordingly, this review summarizes the underlying mechanisms involved in EV targeting and uptake. The primary method of entry by EVs appears to be endocytosis, where clathrin-mediated, caveolae-dependent, macropinocytotic, phagocytotic, and lipid raft-mediated uptake have been variously described as being prevalent. EV uptake mechanisms may depend on proteins and lipids found on the surfaces of both vesicles and target cells. As EVs have been shown to contribute to cancer growth and progression, further exploration and targeting of the gateways utilized by EVs to internalize into tumor cells may assist in the prevention or deceleration of cancer pathogenesis.
Collapse
Affiliation(s)
- Lana Ginini
- Rappaport Family Institute for Research in the Medical Sciences, Technion–Israel Institute of Technology, Haifa 31096, Israel; (L.G.); (E.F.)
| | - Salem Billan
- Head and Neck Institute, The Holy Family Hospital Nazareth, Nazareth 1641100, Israel;
- Medical Oncology and Radiation Therapy Program, Oncology Section, Rambam Health Care Campus, HaAliya HaShniya Street 8, Haifa 3109601, Israel
| | - Eran Fridman
- Rappaport Family Institute for Research in the Medical Sciences, Technion–Israel Institute of Technology, Haifa 31096, Israel; (L.G.); (E.F.)
| | - Ziv Gil
- Head and Neck Institute, The Holy Family Hospital Nazareth, Nazareth 1641100, Israel;
| |
Collapse
|
|
46
|
Extracellular Vesicles Derived from Acidified Metastatic Melanoma Cells Stimulate Growth, Migration, and Stemness of Normal Keratinocytes. Biomedicines 2022; 10:biomedicines10030660. [PMID: 35327461 PMCID: PMC8945455 DOI: 10.3390/biomedicines10030660] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 02/04/2023] Open
Abstract
Metastatic melanoma is a highly malignant tumor. Melanoma cells release extracellular vesicles (EVs), which contribute to the growth, metastasis, and malignancy of neighboring cells by transfer of tumor-promoting miRNAs, mRNA, and proteins. Melanoma microenvironment acidification promotes tumor progression and determines EVs’ properties. We studied the influence of EVs derived from metastatic melanoma cells cultivated at acidic (6.5) and normal (7.4) pH on the morphology and homeostasis of normal keratinocytes. Acidification of metastatic melanoma environment made EVs more prooncogenic with increased expression of prooncogenic mi221 RNA, stemless factor CD133, and pro-migration factor SNAI1, as well as with downregulated antitumor mir7 RNA. Incubation with EVs stimulated growth and migration both of metastatic melanoma cells and keratinocytes and changed the morphology of keratinocytes to stem-like phenotype, which was confirmed by increased expression of the stemness factors KLF and CD133. Activation of the AKT/mTOR and ERK signaling pathways and increased expression of epidermal growth factor receptor EGFR and SNAI1 were detected in keratinocytes upon incubation with EVs. Moreover, EVs reduced the production of different cytokines (IL6, IL10, and IL12) and adhesion factors (sICAM-1, sICAM-3, sPecam-1, and sCD40L) usually secreted by keratinocytes to control melanoma progression. Bioinformatic analysis revealed the correlation between decreased expression of these secreted factors and worse survival prognosis for patients with metastatic melanoma. Altogether, our data mean that metastatic melanoma EVs are important players in the transformation of normal keratinocytes.
Collapse
|
|
47
|
Asare-Werehene M, Tsuyoshi H, Zhang H, Salehi R, Chang CY, Carmona E, Librach CL, Mes-Masson AM, Chang CC, Burger D, Yoshida Y, Tsang BK. Plasma Gelsolin Confers Chemoresistance in Ovarian Cancer by Resetting the Relative Abundance and Function of Macrophage Subtypes. Cancers (Basel) 2022; 14:cancers14041039. [PMID: 35205790 PMCID: PMC8870487 DOI: 10.3390/cancers14041039] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 02/06/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Ovarian cancer is one of the deadliest female cancers with very poor survival, primarily due to late diagnosis, recurrence and chemoresistance. Although the over-expression of plasma gelsolin (pGSN) protects ovarian cancer cells from chemotherapy-induced death, its immunological role in the tumor microenvironment is less explored. Here, we demonstrate that pGSN over-expression downregulates the anti-tumor functions of M1 macrophages, an effect that contributes to chemoresistance and poor patient survival. This study demonstrates the novel inhibitory role of pGSN on tumor-infiltrated M1 macrophages and also offers new insights in maximizing the effectiveness of immunotherapy for ovarian cancer patients. Abstract Ovarian cancer (OVCA) is the most lethal gynaecological cancer with a 5-year survival rate less than 50%. Despite new therapeutic strategies, such as immune checkpoint blockers (ICBs), tumor recurrence and drug resistance remain key obstacles in achieving long-term therapeutic success. Therefore, there is an urgent need to understand the cellular mechanisms of immune dysregulation in chemoresistant OVCA in order to harness the host’s immune system to improve survival. The over-expression of plasma gelsolin (pGSN) mRNA is associated with a poorer prognosis in OVCA patients; however, its immuno-modulatory role has not been elucidated. In this study, for the first time, we report pGSN as an inhibitor of M1 macrophage anti-tumor functions in OVCA chemoresistance. Increased epithelial pGSN expression was associated with the loss of chemoresponsiveness and poor survival. While patients with increased M1 macrophage infiltration exhibited better survival due to nitric-oxide-induced ROS accumulation in OVCA cells, cohorts with poor survival had a higher infiltration of M2 macrophages. Interestingly, increased epithelial pGSN expression was significantly associated with the reduced survival benefits of infiltrated M1 macrophages, through apoptosis via increased caspase-3 activation and reduced production of iNOS and TNFα. Additionally, epithelial pGSN expression was an independent prognostic marker in predicting progression-free survival. These findings support our hypothesis that pGSN is a modulator of inflammation and confers chemoresistance in OVCA, in part by resetting the relative abundance and function of macrophage subtypes in the ovarian tumor microenvironment. Our findings raise the possibility that pGSN may be a potential therapeutic target for immune-mediated chemoresistance in OVCA.
Collapse
Affiliation(s)
- Meshach Asare-Werehene
- Department of Obstetrics & Gynecology, Faculty of Medicine & Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1H 8L1, Canada; (M.A.-W.); (R.S.)
- Department of Cellular and Molecular Medicine & The Centre for Infection, Immunity and Inflammation (CI3), Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada;
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada;
| | - Hideaki Tsuyoshi
- Department of Obstetrics and Gynecology, University of Fukui, Fukui 910-8507, Japan;
| | - Huilin Zhang
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada;
- Department of Obstetrics and Gynecology, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210004, China
| | - Reza Salehi
- Department of Obstetrics & Gynecology, Faculty of Medicine & Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1H 8L1, Canada; (M.A.-W.); (R.S.)
- Department of Cellular and Molecular Medicine & The Centre for Infection, Immunity and Inflammation (CI3), Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada;
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada;
- CReATe Fertility Centre, 790 Bay Street, Suite 1100, Toronto, ON M5G 1N8, Canada;
| | - Chia-Yu Chang
- Department of Biological Science and Technology, Department of Electrophysics and Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan; (C.-Y.C.); (C.-C.C.)
- Institute of Physics, Academia Sinica, Nankang, Taipei 11529, Taiwan
| | - Euridice Carmona
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal and Institut du Cancer de Montréal, Montreal, QC H2X 0A9, Canada; (E.C.); (A.-M.M.-M.)
| | - Clifford L. Librach
- CReATe Fertility Centre, 790 Bay Street, Suite 1100, Toronto, ON M5G 1N8, Canada;
- Departments of Obstetrics & Gynecology and Physiology, Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A1, Canada
| | - Anne-Marie Mes-Masson
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal and Institut du Cancer de Montréal, Montreal, QC H2X 0A9, Canada; (E.C.); (A.-M.M.-M.)
| | - Chia-Ching Chang
- Department of Biological Science and Technology, Department of Electrophysics and Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan; (C.-Y.C.); (C.-C.C.)
- Institute of Physics, Academia Sinica, Nankang, Taipei 11529, Taiwan
| | - Dylan Burger
- Department of Cellular and Molecular Medicine & The Centre for Infection, Immunity and Inflammation (CI3), Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada;
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada;
| | - Yoshio Yoshida
- Department of Obstetrics and Gynecology, University of Fukui, Fukui 910-8507, Japan;
- Correspondence: (Y.Y.); (B.K.T.)
| | - Benjamin K. Tsang
- Department of Obstetrics & Gynecology, Faculty of Medicine & Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1H 8L1, Canada; (M.A.-W.); (R.S.)
- Department of Cellular and Molecular Medicine & The Centre for Infection, Immunity and Inflammation (CI3), Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada;
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada;
- Correspondence: (Y.Y.); (B.K.T.)
| |
Collapse
|
|
48
|
Li X, Wang S, Mu W, Barry J, Han A, Carpenter RL, Jiang BH, Peiper SC, Mahoney MG, Aplin AE, Ren H, He J. Reactive oxygen species reprogram macrophages to suppress antitumor immune response through the exosomal miR-155-5p/PD-L1 pathway. J Exp Clin Cancer Res 2022; 41:41. [PMID: 35086548 PMCID: PMC8793215 DOI: 10.1186/s13046-022-02244-1] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 01/03/2022] [Indexed: 12/13/2022] Open
Abstract
Background Cancer cells have an imbalance in oxidation-reduction (redox) homeostasis. Understanding the precise mechanisms and the impact of the altered redox microenvironment on the immunologic reaction to tumors is limited. Methods We isolated exosomes from ovarian cancer cells through ultracentrifuge and characterized by Western-blots and Nanoparticle Tracking Analysis. 2D, 3D-coculture tumor model, and 3D live cell imaging were used to study the interactions between tumor cells, macrophages and CD3 T cells in vitro. The role of exosomal miR-155-5p in tumor growth was evaluated in xenograft nude mice models and immune-competent mice models. Flow cytometry and flow sorting were used to determine the expression levels of miR-155-5p and PD-L1 in ascites and splenic macrophages, and the percentages of CD3 T cells subpopulations. Results The elevation of reactive oxygen species (ROS) greatly downregulated exosomal miR-155-5p expression in tumor cells. Neutralization of ROS with N-acetyl-L-cysteine (NAC) increased the levels of miR-155-5p in tumor exosomes that were taken up by macrophages, leading to reduction of macrophage migration and tumor spheroid infiltration. We further found that programmed death ligand 1 (PD-L1) is a functional target of miR-155-5p. Co-culture of macrophages pre-treated with NAC-derived tumor exosomes or exosomal miR-155-5p with T-lymphocytes leading to an increased percentage of CD8+ T-lymphocyte and a decreased CD3+ T cell apoptosis through PD-L1 downregulation. Tumor growth in nude mice was delayed by treatment with NAC-derived tumor exosomes. Delivery of tumor exo-miR-155-5p in immune-intact mice suppressed ovarian cancer progression and macrophage infiltration, and activated CD8+ T cell function. It is of note that exo-miR-155-5p inhibited tumor growth more potently than the PD-L1 antibody, suggesting that in addition to PD-L1, other pathways may also be targeted by this approach. Conclusions Our findings demonstrate a novel mechanism, ROS-induced down-regulation of miR-155-5p, by which tumors modulate the microenvironment that favors tumor growth. Understanding of the negative impact of ROS on the tumor immune response will improve current therapeutic strategies. Targeting miR-155-5p can be an alternative approach to prevent formation of an immunosuppressive TME through downregulation of PD-L1 and other immunosuppressive factors. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02244-1.
Collapse
Affiliation(s)
- Xiang Li
- Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA.,Department of Otorhinolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P. R. China
| | - Shaomin Wang
- Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA
| | - Wei Mu
- School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jennifer Barry
- Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA
| | - Anna Han
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA
| | - Richard L Carpenter
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Bloomington, IN, 47405, USA
| | - Bing-Hua Jiang
- Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA
| | - Stephen C Peiper
- Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA
| | - Mỹ G Mahoney
- Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, USA
| | - Andrew E Aplin
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA
| | - Hong Ren
- Department of Thoracic Surgery and Oncology, Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P. R. China.
| | - Jun He
- Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA.
| |
Collapse
|
|
49
|
Yang Z, Wang D, Zhang C, Liu H, Hao M, Kan S, Liu D, Liu W. The Applications of Gold Nanoparticles in the Diagnosis and Treatment of Gastrointestinal Cancer. Front Oncol 2022; 11:819329. [PMID: 35127533 PMCID: PMC8807688 DOI: 10.3389/fonc.2021.819329] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 12/27/2021] [Indexed: 12/14/2022] Open
Abstract
In recent years, the morbidity and mortality of gastrointestinal cancer have remained high in China. Due to the deep location of the gastrointestinal organs, such as gastric cancer, the early symptoms of cancer are not obvious. It is generally discovered at an advanced stage with distant metastasis and lymph node infiltration, making it difficult to cure. Therefore, there is a significant need for novel technologies that can effectively diagnose and treat gastrointestinal cancer, ultimately reducing its mortality. Gold nanoparticles (GNPs), a type of nanocarrier with unique optical properties and remarkable biocompatibility, have the potential to influence the fate of cancer by delivering drugs, nucleic acids to cancer cells and tissues. As a safe and reliable visualization agent, GNPs can track drugs and accurately indicate the location and boundaries of cancer, opening up new possibilities for cancer treatment. In addition, GNPs have been used in photodynamic therapy to deliver photosensitizers, as well as in combination with photothermal therapy. Therefore, GNPs can be used as a safe and effective nanomaterial in the treatment and diagnosis of gastrointestinal cancer.
Collapse
Affiliation(s)
- Zhijing Yang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
| | - Dongxu Wang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Chenyu Zhang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Huimin Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
| | - Ming Hao
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
| | - Shaoning Kan
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
| | - Dianfeng Liu
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Weiwei Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| |
Collapse
|
|
50
|
Exosome as a Delivery Vehicle for Cancer Therapy. Cells 2022; 11:cells11030316. [PMID: 35159126 PMCID: PMC8834560 DOI: 10.3390/cells11030316] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 01/14/2022] [Accepted: 01/17/2022] [Indexed: 02/07/2023] Open
Abstract
Exosomes are small extracellular vesicles that are naturally produced and carry biomolecules such as proteins, microRNAs, and metabolites. Because of their small size and low level of biomolecule expression, the biological function of exosomes has only been identified recently. Despite the short history of investigation, exosomes seem to have remarkable potential as a delivery vehicle. With regards to cancer therapy, numerous antitumor agents demonstrate serious side effects (or toxicity), which has led to the unmet need for improving their selectivity and stability. Exosomes, either produced naturally or generated artificially, provide an attractive platform to load many types of molecules such as small molecules, biologics, and other therapeutic agents. Furthermore, the features of exosomes can be designed by selecting their source cells, or they can be engineered to incorporate affinity tags; thus, exosomes show promise as effective delivery vehicles for the complex tumor microenvironment. In this review, we focus on various exosomes produced from different cell types and their potential uses. Moreover, we summarize the current state of artificial exosomes as a drug carrier and provide an overview of the techniques used for their production.
Collapse
|