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Luo X, McAndrews KM, Kalluri R. Natural and Bioengineered Extracellular Vesicles in Diagnosis, Monitoring and Treatment of Cancer. ACS NANO 2025; 19:5871-5896. [PMID: 39869032 PMCID: PMC12002402 DOI: 10.1021/acsnano.4c11630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Extracellular vesicles (EVs) are cell derived nanovesicles which are implicated in both physiological and pathological intercellular communication, including the initiation, progression, and metastasis of cancer. The exchange of biomolecules between stromal cells and cancer cells via EVs can provide a window to monitor cancer development in real time for better diagnostic and interventional strategies. In addition, the process of secretion and internalization of EVs by stromal and cancer cells in the tumor microenvironment (TME) can be exploited for delivering therapeutics. EVs have the potential to provide a targeted, biocompatible, and efficient delivery platform for the treatment of cancer and other diseases. Natural as well as engineered EVs as nanomedicine have immense potential for disease intervention. Here, we provide an overview of current knowledge of EVs' function in cancer progression, diagnostic and therapeutic applications for EVs in the cancer setting, as well as current EV engineering strategies.
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Affiliation(s)
- Xin Luo
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States
- Department of Bioengineering, Rice University, Houston, Texas 77005, United States
| | - Kathleen M. McAndrews
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States
| | - Raghu Kalluri
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States
- Department of Bioengineering, Rice University, Houston, Texas 77005, United States
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, United States
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Ghosh S, Dey A, Chakrabarti A, Bhuniya T, Indu N, Hait A, Chowdhury A, Paul A, Mahajan AA, Papadakis M, Alexiou A, Jha SK. The theragnostic advances of exosomes in managing leukaemia. J Cell Mol Med 2024; 28:e70052. [PMID: 39659020 PMCID: PMC11632122 DOI: 10.1111/jcmm.70052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 07/21/2024] [Accepted: 08/20/2024] [Indexed: 12/12/2024] Open
Abstract
Leukaemia, a group of haematological malignancies, presents ongoing diagnosis, prognosis, and treatment challenges. A major obstacle in treating this disease is the development of drug resistance. Overcoming drug resistance poses a significant barrier to effective leukaemia treatment. The emergence of exosome research has unveiled new insights into the probable theragnostic implementations in leukaemia. Various research has exhibited the diagnostic possibilities of exosomes in identifying leukaemia-specific biomarkers, including genetic mutations and fusion transcripts. Additionally, exosomes have been implicated in disease progression and treatment response, rendering them appealing targets for therapeutics. Exosomes, originating from diverse cell types, are instrumental in intercellular communication as they participate in the functional transportation of molecules like proteins, nucleic acids and lipids across space. Exosomes have a dual role in immune regulation, mediating immune suppression and modulating anti-leukaemia immune responses. Interestingly, exosomes can even act as drug transport vehicles. This review delves into the intricate process of exosome biogenesis, shedding light on their formation and release from donor cells. The key mechanisms engaged in exosome biogenesis, for instance, the endosomal sorting complexes required for transport (ESCRT) machinery and ESCRT-independent pathways, are thoroughly discussed. Looking ahead, future approaches that leverage innovative technologies hold the promise of revolutionizing disease management and improving patient outcomes.
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Affiliation(s)
- Subhrojyoti Ghosh
- Department of BiotechnologyIndian Institute of Technology MadrasChennaiTamil NaduIndia
| | - Anuvab Dey
- Department of Biosciences and BioengineeringIndian Institute of Technology GuwahatiGuwahatiAssamIndia
| | - Aneshwa Chakrabarti
- Department of Chemistry and Chemical BiologyIndian Institute of Technology, Indian School of Mines DhanbadDhanbadIndia
| | - Tiyasa Bhuniya
- Department of BiotechnologyNIT DurgapurDurgapurWest BengalIndia
| | - Neelparna Indu
- Department of BiotechnologyHeritage Institute of TechnologyKolkataIndia
| | - Anirban Hait
- Department of BiotechnologyHeritage Institute of TechnologyKolkataIndia
| | - Ankita Chowdhury
- Department of BiotechnologyHeritage Institute of TechnologyKolkataIndia
| | - Aritra Paul
- Department of BiotechnologyHeritage Institute of TechnologyKolkataIndia
| | | | - Marios Papadakis
- Department of Surgery IIUniversity Hospital Witten‐HerdeckeWuppertalGermany
| | - Athanasios Alexiou
- University Centre for Research & DevelopmentChandigarh UniversityMohaliPunjabIndia
- Department of Research & DevelopmentFunogenAthensGreece
- Department of Research & DevelopmentAFNP MedWienAustria
- Department of Science and EngineeringNovel Global Community Educational FoundationHebershamNew South WalesAustralia
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Hu C, Chen Q, Wu T, Du X, Dong Y, Peng Z, Xue W, Sunkara V, Cho YK, Dong L. The Role of Extracellular Vesicles in the Treatment of Prostate Cancer. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2311071. [PMID: 38639331 DOI: 10.1002/smll.202311071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 02/26/2024] [Indexed: 04/20/2024]
Abstract
Prostate cancer (PCa) has become a public health concern in elderly men due to an ever-increasing number of estimated cases. Unfortunately, the available treatments are unsatisfactory because of a lack of a durable response, especially in advanced disease states. Extracellular vesicles (EVs) are lipid-bilayer encircled nanoscale vesicles that carry numerous biomolecules (e.g., nucleic acids, proteins, and lipids), mediating the transfer of information. The past decade has witnessed a wide range of EV applications in both diagnostics and therapeutics. First, EV-based non-invasive liquid biopsies provide biomarkers in various clinical scenarios to guide treatment; EVs can facilitate the grading and staging of patients for appropriate treatment selection. Second, EVs play a pivotal role in pathophysiological processes via intercellular communication. Targeting key molecules involved in EV-mediated tumor progression (e.g., proliferation, angiogenesis, metastasis, immune escape, and drug resistance) is a potential approach for curbing PCa. Third, EVs are promising drug carriers. Naïve EVs from various sources and engineered EV-based drug delivery systems have paved the way for the development of new treatment modalities. This review discusses the recent advancements in the application of EV therapies and highlights EV-based functional materials as novel interventions for PCa.
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Affiliation(s)
- Cong Hu
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Qi Chen
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Tianyang Wu
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Xinxing Du
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Yanhao Dong
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Zehong Peng
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Wei Xue
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Vijaya Sunkara
- Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Yoon-Kyoung Cho
- Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
- Center for Algorithmic and Robotized Synthesis, Institute for Basic Science Ulsan, Ulsan, 44919, Republic of Korea
| | - Liang Dong
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
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Zhao R, Liao W, Tan D, Huang H, Hu C, Chen M. Comparative analysis of the expression patterns of TM9SF family members in mice. Gene Expr Patterns 2024; 52:119366. [PMID: 38719197 DOI: 10.1016/j.gep.2024.119366] [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: 11/23/2023] [Revised: 03/05/2024] [Accepted: 05/05/2024] [Indexed: 05/19/2024]
Abstract
Transmembrane 9 superfamily proteins (TM9SFs) define a highly conserved protein family, each member of which is characterized by a variable extracellular domain and presumably nine transmembrane domains. Although previous studies have delineated the potential cytological roles of TM9SFs like autophagy and secretory pathway, their functions during development are largely unknown. To establish the basis for dissecting the functions of TM9SFs in vivo, we employed the open-source database, structure prediction, immunofluorescence and Western blot to describe the gene and protein expression patterns of TM9SFs in human and mouse. While TM9SFs are ubiquitously and homogeneously expressed in all tissues in human with RNA sequencing and proteomics analysis, we found that all mice Tm9sf proteins are preferentially expressed in lung except Tm9sf1 which is enriched in brain although they all distributed in various tissues we examined. In addition, we further explored their expression patterns in the mice central nervous system (CNS) and its extension tissue retina. Interestingly, we could show that Tm9sf1is developmentally up-regulated in brain. In addition, we also detected all Tm9sf proteins are located in neurons and microglia instead of astrocytes. Importantly, Tm9sf3 is localized in the nuclei which is distinct from the other members that are dominantly targeted to the plasma membrane/cytoplasm as expected. Finally, we also found that Tm9sf family members are broadly expressed in the layers of INL, OPL, and GCL of retina and likely targeted to the plasma membrane of retinal cells. Thus, our data provided a comprehensive overview of TM9SFs expression patterns, illustrating their ubiquitous roles in different organs, implying the possible roles of Tm9sf2/3/4 in lung functions and Tm9sf1 in neurodevelopment, and highlighting a unique cell biological functions of TM9SF3 in neuronal and microglia.
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Affiliation(s)
- Rui Zhao
- Guangdong Second Provincial General Hospital, Guangzhou, 510317, China; Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; Institute for Brain Research and Rehabilitation, South China Normal University, 510631, Guangzhou, China
| | - Wenxiong Liao
- Guangdong Second Provincial General Hospital, Guangzhou, 510317, China
| | - Duo Tan
- Guangdong Second Provincial General Hospital, Guangzhou, 510317, China
| | - Haiyou Huang
- Jianghai Street Community Health Service Center, Haizhu District, Guangzhou, Guangzhou, 510305, China
| | - Chun Hu
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; Institute for Brain Research and Rehabilitation, South China Normal University, 510631, Guangzhou, China
| | - Meilan Chen
- Guangdong Second Provincial General Hospital, Guangzhou, 510317, China.
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Smith SF, Brewer DS, Hurst R, Cooper CS. Applications of Urinary Extracellular Vesicles in the Diagnosis and Active Surveillance of Prostate Cancer. Cancers (Basel) 2024; 16:1717. [PMID: 38730670 PMCID: PMC11083542 DOI: 10.3390/cancers16091717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 04/23/2024] [Accepted: 04/24/2024] [Indexed: 05/13/2024] Open
Abstract
Prostate cancer is the most common non-cutaneous cancer among men in the UK, causing significant health and economic burdens. Diagnosis and risk prognostication can be challenging due to the genetic and clinical heterogeneity of prostate cancer as well as uncertainties in our knowledge of the underlying biology and natural history of disease development. Urinary extracellular vesicles (EVs) are microscopic, lipid bilayer defined particles released by cells that carry a variety of molecular cargoes including nucleic acids, proteins and other molecules. Urine is a plentiful source of prostate-derived EVs. In this narrative review, we summarise the evidence on the function of urinary EVs and their applications in the evolving field of prostate cancer diagnostics and active surveillance. EVs are implicated in the development of all hallmarks of prostate cancer, and this knowledge has been applied to the development of multiple diagnostic tests, which are largely based on RNA and miRNA. Common gene probes included in multi-probe tests include PCA3 and ERG, and the miRNAs miR-21 and miR-141. The next decade will likely bring further improvements in the diagnostic accuracy of biomarkers as well as insights into molecular biological mechanisms of action that can be translated into opportunities in precision uro-oncology.
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Affiliation(s)
- Stephanie F. Smith
- Metabolic Health Research Centre, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK (C.S.C.)
- Department of Urology, Norfolk and Norwich University Hospitals, Norwich NR4 7UY, UK
| | - Daniel S. Brewer
- Metabolic Health Research Centre, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK (C.S.C.)
| | - Rachel Hurst
- Metabolic Health Research Centre, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK (C.S.C.)
| | - Colin S. Cooper
- Metabolic Health Research Centre, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK (C.S.C.)
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Gade VKV, Yadav BS. Understanding the role of transmembrane 9 superfamily member 1 in bladder cancer pathogenesis. World J Clin Oncol 2024; 15:468-471. [PMID: 38689631 PMCID: PMC11056861 DOI: 10.5306/wjco.v15.i4.468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 02/16/2024] [Accepted: 03/06/2024] [Indexed: 04/22/2024] Open
Abstract
In this editorial we comment on the article by Wei et al, published in the recent issue of the World Journal of Clinical Oncology. The authors investigated the role of Transmembrane 9 superfamily member 1 (TM9SF1) protein in bladder cancer (BC) carcinogenesis. Lentiviral vectors were used to achieve silencing or overexpression of TM9SF1 gene in three BC cell lines. These cell lines were then subject to cell counting kit 8, wound-healing assay, transwell assay, and flow cytometry. Proliferation, migration, and invasion of BC cells were increased in cell lines subjected to TM9SF1 overexpression. TM9SF1 silencing inhibited proliferation, migration and invasion of BC cells. The authors conclude that TM9SF1 may be an oncogene in bladder cancer pathogenesis.
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Affiliation(s)
- Venkata Krishna Vamsi Gade
- Department of Radiotherapy & Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Budhi Singh Yadav
- Department of Radiotherapy & Oncology, Regional Cancer Centre, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
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Wu Y, Fu H, Hao J, Yang Z, Qiao X, Li Y, Zhao R, Lin T, Wang Y, Wang M. Tumor-derived exosomal PD-L1: a new perspective in PD-1/PD-L1 therapy for lung cancer. Front Immunol 2024; 15:1342728. [PMID: 38562933 PMCID: PMC10982384 DOI: 10.3389/fimmu.2024.1342728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 02/29/2024] [Indexed: 04/04/2024] Open
Abstract
Exosomes play a crucial role in facilitating intercellular communication within organisms. Emerging evidence indicates that a distinct variant of programmed cell death ligand-1 (PD-L1), found on the surface of exosomes, may be responsible for orchestrating systemic immunosuppression that counteracts the efficacy of anti-programmed death-1 (PD-1) checkpoint therapy. Specifically, the presence of PD-L1 on exosomes enables them to selectively target PD-1 on the surface of CD8+ T cells, leading to T cell apoptosis and impeding T cell activation or proliferation. This mechanism allows tumor cells to evade immune pressure during the effector stage. Furthermore, the quantification of exosomal PD-L1 has the potential to serve as an indicator of the dynamic interplay between tumors and immune cells, thereby suggesting the promising utility of exosomes as biomarkers for both cancer diagnosis and PD-1/PD-L1 inhibitor therapy. The emergence of exosomal PD-L1 inhibitors as a viable approach for anti-tumor treatment has garnered significant attention. Depleting exosomal PD-L1 may serve as an effective adjunct therapy to mitigate systemic immunosuppression. This review aims to elucidate recent insights into the role of exosomal PD-L1 in the field of immune oncology, emphasizing its potential as a diagnostic, prognostic, and therapeutic tool in lung cancer.
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Affiliation(s)
- Yunjiao Wu
- Department of Respiratory Medical Oncology, Harbin Medical University Cancer Hospital, Heilongjiang, Harbin, China
| | - Huichao Fu
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Harbin Medical University, Heilongjiang, Harbin, China
| | - Jingwei Hao
- Department of Respiratory Medical Oncology, Harbin Medical University Cancer Hospital, Heilongjiang, Harbin, China
| | - Zhaoyang Yang
- Department of Respiratory Medical Oncology, Harbin Medical University Cancer Hospital, Heilongjiang, Harbin, China
| | - Xinyi Qiao
- Department of Respiratory Medical Oncology, Harbin Medical University Cancer Hospital, Heilongjiang, Harbin, China
| | - Yingjie Li
- Department of Respiratory Medical Oncology, Harbin Medical University Cancer Hospital, Heilongjiang, Harbin, China
| | - Rui Zhao
- Department of Respiratory Medical Oncology, Harbin Medical University Cancer Hospital, Heilongjiang, Harbin, China
| | - Tie Lin
- Department of Surgery, The First Affiliated Hospital of Harbin Medical University, Heilongjiang, Harbin, China
| | - Yicun Wang
- Department of Medical Research Center, Second Hospital of Jilin University, Jilin, Changchun, China
| | - Meng Wang
- Department of Respiratory Medical Oncology, Harbin Medical University Cancer Hospital, Heilongjiang, Harbin, China
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Wei L, Wang SS, Huang ZG, He RQ, Luo JY, Li B, Cheng JW, Wu KJ, Zhou YH, Liu S, Li SH, Chen G. TM9SF1 promotes bladder cancer cell growth and infiltration. World J Clin Oncol 2024; 15:302-316. [PMID: 38455139 PMCID: PMC10915948 DOI: 10.5306/wjco.v15.i2.302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/20/2023] [Accepted: 11/27/2023] [Indexed: 02/20/2024] Open
Abstract
BACKGROUND Bladder cancer (BC) is the most common urological tumor. It has a high recurrence rate, displays tutor heterogeneity, and resists chemotherapy. Furthermore, the long-term survival rate of BC patients has remained unchanged for decades, which seriously affects the quality of patient survival. To improve the survival rate and prognosis of BC patients, it is necessary to explore the molecular mechanisms of BC development and progression and identify targets for treatment and intervention. Transmembrane 9 superfamily member 1 (TM9SF1), also known as MP70 and HMP70, is a member of a family of nine transmembrane superfamily proteins, which was first identified in 1997. TM9SF1 can be expressed in BC, but its biological function and mechanism in BC are not clear. AIM To investigate the biological function and mechanism of TM9SF1 in BC. METHODS Cells at 60%-80% confluence were transfected with lentiviral vectors for 48-72 h to achieve stable TM9SF1 overexpression or silencing in three BC cell lines (5637, T24, and UM-UC-3). The effect of TM9SF1 on the biological behavior of BC cells was then investigated through CCK8, wound-healing assay, transwell assay, and flow cytometry. RESULTS Overexpression of TM9SF1 increased the in vitro proliferation, migration, and invasion of BC cells by promoting the entry of BC cells into the G2/M phase. Silencing of TM9SF1 inhibited in vitro proliferation, migration, and invasion of BC cells and blocked BC cells in the G1 phase. CONCLUSION TM9SF1 may be an oncogene in BC.
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Affiliation(s)
- Long Wei
- Department of Urology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Shi-Shuo Wang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zhi-Guang Huang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Rong-Quan He
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jia-Yuan Luo
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Bin Li
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Ji-Wen Cheng
- Department of Urology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Kun-Jun Wu
- Department of Urology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yu-Hong Zhou
- Department of Urology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Shi Liu
- Department of Urology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Sheng-Hua Li
- Department of Urology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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Zhou SQ, Luo LX. TM9SF1 is implicated in promoting the proliferation and invasion of bladder cancer cells. World J Clin Oncol 2024; 15:175-177. [PMID: 38455138 PMCID: PMC10915938 DOI: 10.5306/wjco.v15.i2.175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 12/27/2023] [Accepted: 01/30/2024] [Indexed: 02/20/2024] Open
Abstract
Zhuo et al looked into the part of transmembrane 9 superfamily member 1 (TM9SF1) in bladder cancer (BC), and evaluated if it can be used as a therapeutic target. They created a permanent BC cell line and tested the effects of TM9SF1 overexpression and suppression on BC cell growth, movement, invasion, and cell cycle advancement. Their results show that TM9SF1 can boost the growth, movement, and invasion of BC cells and their access into the G2/M stage of the cell cycle. This research gives a novel direction and concept for targeted therapy of BC.
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Affiliation(s)
- Shu-Qing Zhou
- The First Clinical College, Guangdong Medical University, Zhanjiang 524023, Guangdong Province, China
| | - Lian-Xiang Luo
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524000, Guangdong Province, China
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Zhao H, Feng K, Lei J, Shu Y, Bo L, Liu Y, Wang L, Liu W, Ning S, Wang L. Identification of somatic mutation-driven enhancers and their clinical utility in breast cancer. iScience 2024; 27:108780. [PMID: 38303701 PMCID: PMC10831879 DOI: 10.1016/j.isci.2024.108780] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 09/04/2023] [Accepted: 01/02/2024] [Indexed: 02/03/2024] Open
Abstract
Somatic mutations contribute to cancer development by altering the activity of enhancers. In the study, a total of 135 mutation-driven enhancers, which displayed significant chromatin accessibility changes, were identified as candidate risk factors for breast cancer (BRCA). Furthermore, we identified four mutation-driven enhancers as independent prognostic factors for BRCA subtypes. In Her2 subtype, enhancer G > C mutation was associated with poorer prognosis through influencing its potential target genes FBXW9, TRIR, and WDR83. We identified aminoglutethimide and quinpirole as candidate drugs targeting the mutated enhancer. In normal subtype, enhancer G > A mutation was associated with poorer prognosis through influencing its target genes ALOX15B, LINC00324, and MPDU1. We identified eight candidate drugs such as erastin, colforsin, and STOCK1N-35874 targeting the mutated enhancer. Our findings suggest that somatic mutations contribute to breast cancer subtype progression by altering enhancer activity, which could be potential candidates for cancer therapy.
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Affiliation(s)
- Hongying Zhao
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China
| | - Ke Feng
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China
| | - Junjie Lei
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yaopeng Shu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China
| | - Lin Bo
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China
| | - Ying Liu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China
| | - Lixia Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China
| | - Wangyang Liu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China
| | - Shangwei Ning
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China
| | - Li Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China
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Azuma K, Ikeda K, Shiba S, Sato W, Horie K, Hasegawa T, Amizuka N, Tanaka S, Inoue S. EBAG9-deficient mice display decreased bone mineral density with suppressed autophagy. iScience 2024; 27:108871. [PMID: 38313054 PMCID: PMC10835455 DOI: 10.1016/j.isci.2024.108871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 11/22/2023] [Accepted: 01/08/2024] [Indexed: 02/06/2024] Open
Abstract
Estrogen receptor-binding fragment associated antigen 9 (EBAG9) exerts tumor-promoting effects by inducing immune escape. We focused on the physiological functions of EBAG9 by investigating the bone phenotypes of Ebag9-knockout mice. Female Ebag9-knockout mice have fragile bones with lower bone mineral density (BMD) compared with wild-type mice. Histomorphometric analyses demonstrated that lower BMD was mainly caused by decreased bone formation. Serum bone turnover markers showed that enhanced bone resorption also contributed to this phenotype. We revealed that EBAG9 promoted autophagy in both osteoblastic and osteoclastic lineages. In addition, the knockdown of Tm9sf1, a gene encoding a protein that functionally interacts with EBAG9, suppressed autophagy and osteoblastic differentiation of the murine preosteoblastic cell line MC3T3-E1. Finally, overexpression of TM9SF1 rescued the suppression of autophagy caused by the silencing of Ebag9. These results suggest that EBAG9 plays a physiological role in bone maintenance by promoting autophagy together with its interactor TM9SF1.
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Affiliation(s)
- Kotaro Azuma
- Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Itabashi-ku, Tokyo 173-0015, Japan
- Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Kazuhiro Ikeda
- Division of Systems Medicine and Gene Therapy, Saitama Medical University, Hidaka, Saitama 350-1241, Japan
| | - Sachiko Shiba
- Division of Systems Medicine and Gene Therapy, Saitama Medical University, Hidaka, Saitama 350-1241, Japan
| | - Wataru Sato
- Division of Systems Medicine and Gene Therapy, Saitama Medical University, Hidaka, Saitama 350-1241, Japan
| | - Kuniko Horie
- Division of Systems Medicine and Gene Therapy, Saitama Medical University, Hidaka, Saitama 350-1241, Japan
| | - Tomoka Hasegawa
- Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Hokkaido 060-8586, Japan
| | - Norio Amizuka
- Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Hokkaido 060-8586, Japan
| | - Shinya Tanaka
- Department of Orthopedic Surgery, Saitama Medical University, Moroyama, Saitama 350-0495, Japan
- Department of Orthopedic Surgery, Japan Community Health Care Organization Saitama Northern Medical Center, Saitama, Saitama 331-8625, Japan
| | - Satoshi Inoue
- Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Itabashi-ku, Tokyo 173-0015, Japan
- Division of Systems Medicine and Gene Therapy, Saitama Medical University, Hidaka, Saitama 350-1241, Japan
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12
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Chen H, Pang B, Zhou C, Han M, Gong J, Li Y, Jiang J. Prostate cancer-derived small extracellular vesicle proteins: the hope in diagnosis, prognosis, and therapeutics. J Nanobiotechnology 2023; 21:480. [PMID: 38093355 PMCID: PMC10720096 DOI: 10.1186/s12951-023-02219-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 11/18/2023] [Indexed: 12/17/2023] Open
Abstract
Current diagnostic tools for prostate cancer (PCa) diagnosis and risk stratification are insufficient. The hidden onset and poor efficacy of traditional therapies against metastatic PCa make this disease a heavy burden in global men's health. Prostate cancer-derived extracellular vesicles (PCDEVs) have garnered attention in recent years due to their important role in communications in tumor microenvironment. Recent advancements have demonstrated PCDEVs proteins play an important role in PCa invasion, progression, metastasis, therapeutic resistance, and immune escape. In this review, we briefly discuss the applications of sEV proteins in PCa diagnosis and prognosis in liquid biopsy, focus on the roles of the PCa-derived small EVs (sEVs) proteins in tumor microenvironment associated with cancer progression, and explore the therapeutic potential of sEV proteins applied for future metastatic PCa therapy.
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Affiliation(s)
- Haotian Chen
- Health Science Center, Ningbo University, Ningbo, 315211, Zhejiang, People's Republic of China
- Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang, People's Republic of China
- Translational Research Laboratory for Urology, Department of Urology, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang, People's Republic of China
| | - Bairen Pang
- Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang, People's Republic of China
- Translational Research Laboratory for Urology, Department of Urology, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang, People's Republic of China
| | - Cheng Zhou
- Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang, People's Republic of China
- Translational Research Laboratory for Urology, Department of Urology, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang, People's Republic of China
| | - Meng Han
- Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang, People's Republic of China
- Translational Research Laboratory for Urology, Department of Urology, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang, People's Republic of China
| | - Jie Gong
- Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang, People's Republic of China
- Translational Research Laboratory for Urology, Department of Urology, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang, People's Republic of China
| | - Yong Li
- Cancer Care Centre, St George Hospital, Kogarah, NSW, 2217, Australia.
- School of Clinical Medicine, St. George and Sutherland Clinical Campuses, UNSW Sydney, Kensington, NSW, 2052, Australia.
| | - Junhui Jiang
- Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang, People's Republic of China.
- Translational Research Laboratory for Urology, Department of Urology, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang, People's Republic of China.
- Department of Urology, Ningbo First Hospital, The First Affiliated Hospital of Ningbo University, Haishu District, Ningbo, 315600, Zhejiang, People's Republic of China.
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13
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Li W, Zhao B, Wang Q, Lu J, Wu X, Chen X. Integrated analysis of tumour-derived exosome-related immune genes to predict progression and immune status of hepatocellular carcinoma. Clin Immunol 2023; 256:109774. [PMID: 37774907 DOI: 10.1016/j.clim.2023.109774] [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: 08/09/2023] [Revised: 09/01/2023] [Accepted: 09/12/2023] [Indexed: 10/01/2023]
Abstract
Tumour-derived exosomes (TDEs) play an important role in tumourigenesis and progression by regulating components in the tumour microenvironment (TME), however, the role of TDE-related immune genes in hepatocellular carcinoma is not fully known. We systematically analysed TDE genes from ExoCarta and immune genes from Immport,Machine learning ultimately identified eight TDE-related prognostic immune genes and used them as the basis for constructing a risk model, which was constructed to better predict patients with hepatocellular carcinoma (HCC) compared with published prognostic models. There were significant differences between the high and low risk groups in terms of biological functioning. Low-risk group were more sensitive to immunotherapy, the sensitivity to oxaliplatin and cisplatin differed between the high- and low-risk groups, and knockout of the core gene RAC1 limited the malignant biological behaviour of hepatocellular carcinoma cells. In conclusion, TIRGs are effective in predicting the prognosis of patients with hepatocellular carcinoma and provide a new perspective on immunotherapy and chemotherapy for patients.
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Affiliation(s)
- Wenhua Li
- Shihezi University School of Medicine, Shihezi 832000, China; Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi 832000, China
| | - Bin Zhao
- Shihezi University School of Medicine, Shihezi 832000, China; Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi 832000, China
| | - Qianwen Wang
- Shihezi University School of Medicine, Shihezi 832000, China; Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi 832000, China
| | - Junxia Lu
- Shihezi University School of Medicine, Shihezi 832000, China; Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi 832000, China
| | - Xiangwei Wu
- Shihezi University School of Medicine, Shihezi 832000, China; The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi 832000, China; Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi 832000, China.
| | - Xueling Chen
- Shihezi University School of Medicine, Shihezi 832000, China; Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi 832000, China.
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14
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Jiang Z, Pan J, Lu J, Mei J, Xu R, Xia D, Yang X, Wang H, Liu C, Xu J, Ding J. NEUROD1 predicts better prognosis in pancreatic cancer revealed by a TILs-based prognostic signature. Front Pharmacol 2022; 13:1025921. [PMID: 36313290 PMCID: PMC9612957 DOI: 10.3389/fphar.2022.1025921] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 09/26/2022] [Indexed: 11/29/2022] Open
Abstract
It has been well-defined that tumor-infiltrating lymphocytes (TILs) play critical roles in pancreatic cancer (PaCa) progression. This research aimed to comprehensively explore the composition of TILs in PaCa and their potential clinical significance. A total of 178 samples from the TCGA and 63 samples from the GSE57495 dataset were enrolled in our study. ImmuCellAI was applied to calculate the infiltrating abundance of 24 immune cell types in PaCa and further survival analysis revealed the prognostic values of TILs in PaCa. Moreover, the Hallmark enticement analysis of differentially expressed genes (DEGs) between low- and high-risk groups was performed as well. Immunohistochemistry staining was used to evaluate NEUROD1 expression. As result, different kinds of TILs had distinct infiltrating features. In addition, Specific TILs subsets had notable prognostic values in PaCa. We further established a 6-TILs signature to assess the prognosis of PaCa patients. Kaplan-Meier and Cox regression analyses both suggested the significant prognostic value of the signature in PaCa. Based on the prognostic signature, we screened a great deal of potential prognostic biomarkers and successfully validated NEUROD1 as a novel prognostic biomarker in PaCa. Overall, the current study illuminated the immune cells infiltrating the landscape in PaCa and identified a TILs-dependent signature and NEUROD1 for prognostic prediction in PaCa patients.
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Affiliation(s)
- Zhiyang Jiang
- Department of General Surgery, Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
| | - Jiadong Pan
- Department of Gastroenterology, Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
| | - Jiahui Lu
- Department of Oncology, Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
| | - Jie Mei
- Department of Oncology, Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
| | - Rui Xu
- The First College of Clinical Medicine of Nanjing Medical University, Nanjing, China
| | - Dandan Xia
- Department of Oncology, Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
| | - Xuejing Yang
- Department of Oncology, Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
| | - Huiyu Wang
- Department of Oncology, Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
| | - Chaoying Liu
- Department of Oncology, Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
| | - Junying Xu
- Department of Oncology, Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
| | - Junli Ding
- Department of Oncology, Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
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15
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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.
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16
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Exosomes carrying immune checkpoints, a promising therapeutic approach in cancer treatment. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:183. [PMID: 36071295 DOI: 10.1007/s12032-022-01781-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 06/20/2022] [Indexed: 10/14/2022]
Abstract
Exosomes are a subgroup of extracellular vesicles generated by distinct cells. Tumor-derived extracellular vesicles convey immunological checkpoint molecules. TEXs as critical mediators in tumor development, metastasis, and immune escape have recently become the focus of scientific research. Exosomes are involved in the regulation of the immune system. Exosomes interact with target cells in the tumor microenvironment, changing their function based on the cargo they contain. Exosomal immune checkpoints might be exploited to track tumor immune evasion, treatment response, and patient prognosis while enhancing tumor cell proliferation and spread. This review focuses on tumor-derived exosomes, their immunosuppressive effects in mice models, and their role in cancer immunotherapy. Exosomes are being studied as possible cancer vaccines, with numerous uses in tumor immunotherapy. Exosomes can carry chemotherapeutics, siRNA, and monoclonal antibodies. Exosomes produced by macrophages might be used to treat cancer. These and other clinical consequences provide new doors for cancer treatment.
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17
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Liu C, He D, Li L, Zhang S, Wang L, Fan Z, Wang Y. Extracellular vesicles in pancreatic cancer immune escape: Emerging roles and mechanisms. Pharmacol Res 2022; 183:106364. [PMID: 35901939 DOI: 10.1016/j.phrs.2022.106364] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/18/2022] [Accepted: 07/22/2022] [Indexed: 11/25/2022]
Abstract
Pancreatic cancer (PC) is the most lethal malignancy worldwide due to its delayed diagnosis and limited treatment options. Despite great progress in clinical trials of immunotherapies for various cancers, their effectiveness in PC is very low, indicating that immune evasion is still a major obstacle to immunotherapy in PC. However, the mechanism of immune escape in PC is not fully understood, which substantially restricts the development of immunotherapy. As an important component of intercellular communication networks, extracellular vesicles (EVs) have attracted increasing attention in relation to immune escape. This review aims to provide a better understanding of the roles of EVs in tumor immune escape and the potential to expand their application in cancer immunotherapy. The relationship between PC and the tumor immune microenvironment is briefly introduced. Then, the mechanism by which EVs are involved in immune regulation is summarized, and the latest progress in determining the role of EVs in regulating PC immune escape is highlighted.
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Affiliation(s)
- Chunping Liu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China.
| | - Dongyue He
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Longmei Li
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shihui Zhang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lei Wang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhijin Fan
- School of Medicine, South China University of Technology, Guangzhou, China.
| | - Yichao Wang
- Department of Clinical Laboratory Medicine, Tai Zhou Central Hospital (Taizhou University Hospital), No.999 Donghai Road, Jiaojiang District, Taizhou, Zhejiang 318000, China.
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18
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Mousavi SM, Amin Mahdian SM, Ebrahimi MS, Taghizadieh M, Vosough M, Sadri Nahand J, Hosseindoost S, Vousooghi N, Javar HA, Larijani B, Hadjighassem MR, Rahimian N, Hamblin MR, Mirzaei H. Microfluidics for detection of exosomes and microRNAs in cancer: State of the art. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 28:758-791. [PMID: 35664698 PMCID: PMC9130092 DOI: 10.1016/j.omtn.2022.04.011] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Exosomes are small extracellular vesicles with sizes ranging from 30-150 nanometers that contain proteins, lipids, mRNAs, microRNAs, and double-stranded DNA derived from the cells of origin. Exosomes can be taken up by target cells, acting as a means of cell-to-cell communication. The discovery of these vesicles in body fluids and their participation in cell communication has led to major breakthroughs in diagnosis, prognosis, and treatment of several conditions (e.g., cancer). However, conventional isolation and evaluation of exosomes and their microRNA content suffers from high cost, lengthy processes, difficult standardization, low purity, and poor yield. The emergence of microfluidics devices with increased efficiency in sieving, trapping, and immunological separation of small volumes could provide improved detection and monitoring of exosomes involved in cancer. Microfluidics techniques hold promise for advances in development of diagnostic and prognostic devices. This review covers ongoing research on microfluidics devices for detection of microRNAs and exosomes as biomarkers and their translation to point-of-care and clinical applications.
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Affiliation(s)
- Seyed Mojtaba Mousavi
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Amin Mahdian
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Saeid Ebrahimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Center for Women’s Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 1665659911, Iran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saereh Hosseindoost
- Pain Research Center, Neuroscience Institute, Tehran University of Medical Science, Tehran, Iran
| | - Nasim Vousooghi
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Cognitive and Behavioral Sciences, Tehran University of Medical Sciences, Tehran, Iran
- Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Akbari Javar
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmoud Reza Hadjighassem
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Brain and Spinal Cord Research Center, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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19
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Zhuo W, Sun M, Wang K, Zhang L, Li K, Yi D, Li M, Sun Q, Ma X, Liu W, Teng L, Yi C, Zhou T. m 6Am methyltransferase PCIF1 is essential for aggressiveness of gastric cancer cells by inhibiting TM9SF1 mRNA translation. Cell Discov 2022; 8:48. [PMID: 35597784 PMCID: PMC9124189 DOI: 10.1038/s41421-022-00395-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 03/09/2022] [Indexed: 12/12/2022] Open
Abstract
PCIF1 (phosphorylated CTD interacting factor 1) is the first reported RNA N6,2′-O-dimethyladenosine (m6Am) methyltransferase. However, the pathological significance of PCIF1 and m6Am modification remains unknown. Here we find that both PCIF1 expression and m6Am modification are significantly elevated in gastric cancer tissues. Increased PCIF1 is associated with gastric cancer progression, and predicts poor prognosis. Silence of PCIF1 inhibits the proliferation and invasion of gastric cancer cells, and suppresses tumor growth and metastasis in mouse model. m6Am-seq analysis reveals TM9SF1 (transmembrane 9 superfamily member 1) as a target of PCIF1. PCIF1 modifies TM9SF1 mRNA with m6Am leading to decreased TM9SF1 translation. TM9SF1 reverses the effects of PCIF1 on gastric cancer cell aggressiveness. Collectively, our work uncovers an oncogenic function of PCIF1, providing insights into the critical role of m6Am modification in cancer progression.
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Affiliation(s)
- Wei Zhuo
- Department of Cell Biology and Department of Gastroenterology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Meng Sun
- Department of Cell Biology and Department of Gastroenterology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kun Wang
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.,Department of Chemical Biology and Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing, China
| | - Lu Zhang
- Department of Cell Biology and Department of Gastroenterology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Cancer Center, Zhejiang University, Hangzhou, China
| | - Kai Li
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.,Department of Chemical Biology and Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing, China
| | - Danyang Yi
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.,Department of Chemical Biology and Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing, China
| | - Mengjie Li
- Department of Cell Biology and Department of Gastroenterology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Cancer Center, Zhejiang University, Hangzhou, China
| | - Qiang Sun
- Department of Cell Biology and Department of Gastroenterology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Cancer Center, Zhejiang University, Hangzhou, China
| | - Xixi Ma
- Department of Cell Biology and Department of Gastroenterology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Cancer Center, Zhejiang University, Hangzhou, China
| | - Wei Liu
- Department of Cell Biology and Department of Gastroenterology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lisong Teng
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chengqi Yi
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China. .,Department of Chemical Biology and Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
| | - Tianhua Zhou
- Department of Cell Biology and Department of Gastroenterology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. .,Cancer Center, Zhejiang University, Hangzhou, China. .,Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
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20
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Qiao L, Chen Y, Liang N, Xie J, Deng G, Chen F, Wang X, Liu F, Li Y, Zhang J. Targeting Epithelial-to-Mesenchymal Transition in Radioresistance: Crosslinked Mechanisms and Strategies. Front Oncol 2022; 12:775238. [PMID: 35251963 PMCID: PMC8888452 DOI: 10.3389/fonc.2022.775238] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
Radiotherapy exerts a crucial role in curing cancer, however, its treatment efficiency is mostly limited due to the presence of radioresistance. Epithelial-to-mesenchymal transition (EMT) is a biological process that endows the cancer cells with invasive and metastatic properties, as well as radioresistance. Many potential mechanisms of EMT-related radioresistance being reported have broaden our cognition, and hint us the importance of an overall understanding of the relationship between EMT and radioresistance. This review focuses on the recent progresses involved in EMT-related mechanisms in regulating radioresistance, irradiation-mediated EMT program, and the intervention strategies to increase tumor radiosensitivity, in order to improve radiotherapy efficiency and clinical outcomes of cancer patients.
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Affiliation(s)
- Lili Qiao
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Yanfei Chen
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Ning Liang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Jian Xie
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Guodong Deng
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Fangjie Chen
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Xiaojuan Wang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Fengjun Liu
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Yupeng Li
- Department of Oncology, Shandong First Medical University, Jinan, China.,Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Jiandong Zhang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
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21
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Liu K, Jiao YL, Shen LQ, Chen P, Zhao Y, Li MX, Gu BL, Lan ZJ, Ruan HJ, Liu QW, Xu FB, Yuan X, Qi YJ, Gao SG. A Prognostic Model Based on mRNA Expression Analysis of Esophageal Squamous Cell Carcinoma. Front Bioeng Biotechnol 2022; 10:823619. [PMID: 35299644 PMCID: PMC8921680 DOI: 10.3389/fbioe.2022.823619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 01/31/2022] [Indexed: 11/13/2022] Open
Abstract
Background: The aim of this study was to identify prognostic markers for esophageal squamous cell carcinoma (ESCC) and build an effective prognostic nomogram for ESCC.Methods: A total of 365 patients with ESCC from three medical centers were divided into four cohorts. In the discovery phase of the study, we analyzed transcriptional data from 179 cancer tissue samples and identified nine marker genes using edgeR and rbsurv packages. In the training phase, penalized Cox regression was used to select the best marker genes and clinical characteristics in the 179 samples. In the verification phase, these marker genes and clinical characteristics were verified by internal validation cohort (n = 58) and two external cohorts (n = 81, n = 105).Results: We constructed and verified a nomogram model based on multiple clinicopathologic characteristics and gene expression of a patient cohort undergoing esophagectomy and adjuvant radiochemotherapy. The predictive accuracy for 4-year overall survival (OS) indicated by the C-index was 0.75 (95% CI, 0.72–0.78), which was statistically significantly higher than that of the American Joint Committee on Cancer (AJCC) seventh edition (0.65). Furthermore, we found two marker genes (TM9SF1, PDZK1IP) directly related to the OS of esophageal cancer.Conclusion: The nomogram presented in this study can accurately and impersonally predict the prognosis of ESCC patients after partial resection of the esophagus. More research is required to determine whether it can be applied to other patient populations. Moreover, we found two marker genes directly related to the prognosis of ESCC, which will provide a basis for future research.
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Affiliation(s)
- Ke Liu
- School of Information Engineering, Henan University of Science and Technology, Luoyang, China
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital (College of Clinical Medicine) of Henan University of Science and Technology, Luoyang, China
| | - Ye-Lin Jiao
- Department of Pathology, Luo Yang First Peoples’s Hospital, Luoyang, China
| | - Liu-Qing Shen
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital (College of Clinical Medicine) of Henan University of Science and Technology, Luoyang, China
| | - Pan Chen
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital (College of Clinical Medicine) of Henan University of Science and Technology, Luoyang, China
| | - Ying Zhao
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital (College of Clinical Medicine) of Henan University of Science and Technology, Luoyang, China
| | - Meng-Xiang Li
- School of Information Engineering, Henan University of Science and Technology, Luoyang, China
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital (College of Clinical Medicine) of Henan University of Science and Technology, Luoyang, China
| | - Bian-Li Gu
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital (College of Clinical Medicine) of Henan University of Science and Technology, Luoyang, China
| | - Zi-Jun Lan
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital (College of Clinical Medicine) of Henan University of Science and Technology, Luoyang, China
| | - Hao-Jie Ruan
- School of Information Engineering, Henan University of Science and Technology, Luoyang, China
| | - Qi-Wei Liu
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital (College of Clinical Medicine) of Henan University of Science and Technology, Luoyang, China
| | - Feng-Bo Xu
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital (College of Clinical Medicine) of Henan University of Science and Technology, Luoyang, China
| | - Xiang Yuan
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital (College of Clinical Medicine) of Henan University of Science and Technology, Luoyang, China
| | - Yi-Jun Qi
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital (College of Clinical Medicine) of Henan University of Science and Technology, Luoyang, China
- *Correspondence: She-Gan Gao, ; Yi-Jun Qi,
| | - She-Gan Gao
- School of Information Engineering, Henan University of Science and Technology, Luoyang, China
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital (College of Clinical Medicine) of Henan University of Science and Technology, Luoyang, China
- *Correspondence: She-Gan Gao, ; Yi-Jun Qi,
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Hao Q, Wu Y, Wu Y, Wang P, Vadgama JV. Tumor-Derived Exosomes in Tumor-Induced Immune Suppression. Int J Mol Sci 2022; 23:1461. [PMID: 35163380 PMCID: PMC8836190 DOI: 10.3390/ijms23031461] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/19/2022] [Accepted: 01/25/2022] [Indexed: 02/07/2023] Open
Abstract
Exosomes are a class of small membrane-bound extracellular vesicles released by almost all cell types and present in all body fluids. Based on the studies of exosome content and their interactions with recipient cells, exosomes are now thought to mediate "targeted" information transfer. Tumor-derived exosomes (TEX) carry a cargo of molecules different from that of normal cell-derived exosomes. TEX functions to mediate distinct biological effects such as receptor discharge and intercellular cross-talk. The immune system defenses, which may initially restrict tumor progression, are progressively blunted by the broad array of TEX molecules that activate suppressive pathways in different immune cells. Herein, we provide a review of the latest research progress on TEX in the context of tumor-mediated immune suppression and discuss the potential as well as challenges of TEX as a target of immunotherapy.
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Affiliation(s)
- Qiongyu Hao
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; (Y.W.); (Y.W.)
| | - Yong Wu
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; (Y.W.); (Y.W.)
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Yanyuan Wu
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; (Y.W.); (Y.W.)
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Piwen Wang
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; (Y.W.); (Y.W.)
| | - Jaydutt V. Vadgama
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; (Y.W.); (Y.W.)
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
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23
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Xing C, Li H, Li RJ, Yin L, Zhang HF, Huang ZN, Cheng Z, Li J, Wang ZH, Peng HL. The roles of exosomal immune checkpoint proteins in tumors. Mil Med Res 2021; 8:56. [PMID: 34743730 PMCID: PMC8573946 DOI: 10.1186/s40779-021-00350-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 10/19/2021] [Indexed: 02/08/2023] Open
Abstract
Targeting immune checkpoints has achieved great therapeutic effects in the treatment of early-stage tumors. However, most patients develop adaptive resistance to this therapy. The latest evidence demonstrates that tumor-derived exosomes may play a key role in systemic immune suppression and tumor progression. In this article, we highlight the role of exosomal immune checkpoint proteins in tumor immunity, with an emphasis on programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), as well as emerging evidence on roles of T cell immunoglobulin-3 (TIM-3), arginase 1 (ARG1), and estrogen receptor binding fragment-associated antigen 9 (EBAG9) expressed by exosomes.
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Affiliation(s)
- Cheng Xing
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
| | - Heng Li
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
| | - Rui-Juan Li
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
| | - Le Yin
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
| | - Hui-Fang Zhang
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
| | - Zi-Neng Huang
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
| | - Zhao Cheng
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
| | - Ji Li
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
| | - Zhi-Hua Wang
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
| | - Hong-Ling Peng
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, Changsha, 410011 China
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24
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Xia Z, Qing B, Wang W, Gu L, Chen H, Yuan Y. Formation, contents, functions of exosomes and their potential in lung cancer diagnostics and therapeutics. Thorac Cancer 2021; 12:3088-3100. [PMID: 34734680 PMCID: PMC8636224 DOI: 10.1111/1759-7714.14217] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/18/2021] [Accepted: 10/19/2021] [Indexed: 02/06/2023] Open
Abstract
Lung cancer is the leading cause of cancer-related death worldwide due to diagnosis in the advanced stage and drug resistance in the subsequent treatments. Development of novel diagnostic and therapeutic methods is urged to improve the disease outcome. Exosomes are nano-sized vehicles which transport different types of biomolecules intercellularly, including DNA, RNA and proteins, and are implicated in cross-talk between cells and their surrounding microenvironment. Tumor-derived exosomes (TEXs) have been revealed to strongly influence the tumor microenvironment, antitumor immunoregulatory activities, tumor progression and metastasis. Potential of TEXs as biomarkers for lung cancer diagnosis, prognosis and treatment prediction is supported by numerous studies. Moreover, exosomes have been proposed to be promising drug carriers. Here, we review the mechanisms of exosomal formation and uptake, the functions of exosomes in carcinogenesis, and potential clinical utility of exosomes as biomarkers, tumor vaccine and drug delivery vehicles in the diagnosis and therapeutics of lung cancer.
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Affiliation(s)
- Zhenkun Xia
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Bei Qing
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Wei Wang
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Linguo Gu
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Hongzuo Chen
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yunchang Yuan
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
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25
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Ma F, Vayalil J, Lee G, Wang Y, Peng G. Emerging role of tumor-derived extracellular vesicles in T cell suppression and dysfunction in the tumor microenvironment. J Immunother Cancer 2021; 9:jitc-2021-003217. [PMID: 34642246 PMCID: PMC8513270 DOI: 10.1136/jitc-2021-003217] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/19/2021] [Indexed: 02/07/2023] Open
Abstract
Immunotherapeutic drugs including immune checkpoint blockade antibodies have been approved to treat patients in many types of cancers. However, some patients have little or no reaction to the immunotherapy drugs. The mechanisms underlying resistance to tumor immunotherapy are complicated and involve multiple aspects, including tumor-intrinsic factors, formation of immunosuppressive microenvironment, and alteration of tumor and stromal cell metabolism in the tumor microenvironment. T cell is critical and participates in every aspect of antitumor response, and T cell dysfunction is a severe barrier for effective immunotherapy for cancer. Emerging evidence indicates that extracellular vesicles (EVs) secreted by tumor is one of the major factors that can induce T cell dysfunction. Tumor-derived EVs are widely distributed in serum, tissues, and the tumor microenvironment of patients with cancer, which serve as important communication vehicles for cancer cells. In addition, tumor-derived EVs can carry a variety of immune suppressive signals driving T cell dysfunction for tumor immunity. In this review, we explore the potential mechanisms employed by tumor-derived EVs to control T cell development and effector function within the tumor microenvironment. Especially, we focus on current understanding of how tumor-derived EVs molecularly and metabolically reprogram T cell fates and functions for tumor immunity. In addition, we discuss potential translations of targeting tumor-derived EVs to reconstitute suppressive tumor microenvironment or to develop antigen-based vaccines and drug delivery systems for cancer immunotherapy.
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Affiliation(s)
- Feiya Ma
- Biology, Saint Louis University, Saint Louis, Missouri, USA
| | - Jensen Vayalil
- Biology, Saint Louis University, Saint Louis, Missouri, USA
| | - Grace Lee
- Biology, Saint Louis University, Saint Louis, Missouri, USA
| | - Yuqi Wang
- Biology, Saint Louis University, Saint Louis, Missouri, USA
| | - Guangyong Peng
- Internal Medicine, Saint Louis University, Saint Louis, Missouri, USA
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26
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Identification and Validation of Autophagy-Related Gene Nomograms to Predict the Prognostic Value of Patients with Cervical Cancer. JOURNAL OF ONCOLOGY 2021; 2021:5583400. [PMID: 34257653 PMCID: PMC8253645 DOI: 10.1155/2021/5583400] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 05/21/2021] [Accepted: 06/14/2021] [Indexed: 01/06/2023]
Abstract
Autophagy is a process of engulfing one's own cytoplasmic proteins or organelles and coating them into vesicles, fusing with lysosomes to form autophagic lysosomes, and degrading the contents it encapsulates. Increasing studies have shown that autophagy disorders are closely related to the occurrence of tumors. However, the prognostic role of autophagy genes in cervical cancer is still unclear. In this study, we constructed risk signatures of autophagy-related genes (ARGs) to predict the prognosis of cervical cancer. The expression profiles and clinical information of autophagy gene sets were downloaded from TCGA and GSE52903 queues as training and validation sets. The normal cervical tissue expression profile data from the UCSC XENA website (obtained from GTEx) were used as a supplement to the TCGA normal cervical tissue. Univariate COX regression analysis of 17 different autophagy genes was performed with the consensus approach. Tumor samples from TCGA were divided into six subtypes, and the clinical traits of the six subtypes had different distributions. Further absolute shrinkage and selection operator (LASSO) and multivariable COX regression yielded an autophagy genetic risk model consisting of eight genes. In the training set, the survival rate of the high-risk group was lower than that of the low-risk group (p < 0.0001). In the validation set, the AUC area of the receiver operating characteristic (ROC) curve was 0.772 for the training set and 0.889 for the verification set. We found that high and low risk scores were closely related to TNM stage (p < 0.05). The nomogram shows that the risk score combined with other indicators, such as G, T, M, and N, better predicts 1-, 3-, and 5-year survival rates. Decline curve analysis (DCA) shows that the risk model combined with other indicators produces better clinical efficacy. Immune cells with an enrichment score of 28 showed statistically significant differences related to high and low risk. GSEA enrichment analysis showed the main enrichment being in KRAS activation, genes defining epithelial and mesenchymal transition (EMT), raised in response to the low oxygen level (hypoxia) gene and NF-kB in response to TNF. These pathways are closely related to the occurrence of tumors. Our constructed autophagy risk signature may be a prognostic tool for cervical cancer.
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27
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Exploring interactions between extracellular vesicles and cells for innovative drug delivery system design. Adv Drug Deliv Rev 2021; 173:252-278. [PMID: 33798644 DOI: 10.1016/j.addr.2021.03.017] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/15/2021] [Accepted: 03/25/2021] [Indexed: 02/06/2023]
Abstract
Extracellular vesicles (EVs) are submicron cell-secreted structures containing proteins, nucleic acids and lipids. EVs can functionally transfer these cargoes from one cell to another to modulate physiological and pathological processes. Due to their presumed biocompatibility and capacity to circumvent canonical delivery barriers encountered by synthetic drug delivery systems, EVs have attracted considerable interest as drug delivery vehicles. However, it is unclear which mechanisms and molecules orchestrate EV-mediated cargo delivery to recipient cells. Here, we review how EV properties have been exploited to improve the efficacy of small molecule drugs. Furthermore, we explore which EV surface molecules could be directly or indirectly involved in EV-mediated cargo transfer to recipient cells and discuss the cellular reporter systems with which such transfer can be studied. Finally, we elaborate on currently identified cellular processes involved in EV cargo delivery. Through these topics, we provide insights in critical effectors in the EV-cell interface which may be exploited in nature-inspired drug delivery strategies.
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28
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Brożyna AA, Kim TK, Zabłocka M, Jóźwicki W, Yue J, Tuckey RC, Jetten AM, Slominski AT. Association among Vitamin D, Retinoic Acid-Related Orphan Receptors, and Vitamin D Hydroxyderivatives in Ovarian Cancer. Nutrients 2020; 12:E3541. [PMID: 33227893 PMCID: PMC7699234 DOI: 10.3390/nu12113541] [Citation(s) in RCA: 10] [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: 10/15/2020] [Revised: 11/08/2020] [Accepted: 11/12/2020] [Indexed: 12/12/2022] Open
Abstract
Vitamin D and its derivatives, acting via the vitamin D receptor (VDR) and retinoic acid-related orphan receptors γ and α (RORγ and RORα), show anticancer properties. Since pathological conditions are characterized by disturbances in the expression of these receptors, in this study, we investigated their expression in ovarian cancers (OCs), as well as explored the phenotypic effects of vitamin D hydroxyderivatives and RORγ/α agonists on OC cells. The VDR and RORγ showed both a nuclear and a cytoplasmic location, and their expression levels were found to be reduced in the primary and metastatic OCs in comparison to normal ovarian epithelium, as well as correlated to the tumor grade. This reduction in VDR and RORγ expression correlated with a shorter overall disease-free survival. VDR, RORγ, and RORα were also detected in SKOV-3 and OVCAR-3 cell lines with increased expression in the latter line. 20-Hydroxy-lumisterol3 (20(OH)L3) and synthetic RORα/RORγ agonist SR1078 inhibited proliferation only in the OVCAR-3 line, while 20-hydroxyvitamin-D3 (20(OH)D3) only inhibited SKOV-3 cell proliferation. 1,25(OH)2D3, 20(OH)L3, and SR1078, but not 20(OH)D3, inhibited spheroid formation in SKOV-3 cells. In summary, decreases in VDR, RORγ, and RORα expression correlated with an unfavorable outcome for OC, and compounds targeting these receptors had a context-dependent anti-tumor activity in vitro. We conclude that VDR and RORγ expression can be used in the diagnosis and prognosis of OC and suggest their ligands as potential candidates for OC therapy.
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Affiliation(s)
- Anna A. Brożyna
- Department of Human Biology, Institute of Biology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, 87-100 Toruń, Poland
| | - Tae-Kang Kim
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Marzena Zabłocka
- Department of Tumor Pathology and Pathomorphology, Oncology Centre—Prof. Franciszek Łukaszczyk Memorial Hospital in Bydgoszcz, 85-796 Bydgoszcz, Poland;
| | - Wojciech Jóźwicki
- Department of Tumor Pathology and Pathomorphology, Department of Oncology, Faculty of Health Sciences, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 87-100 Torun, Poland;
| | - Junming Yue
- Department of Pathology, University of Tennessee Health Science Center, Memphis, TN 38163, USA;
| | - Robert C. Tuckey
- School of Molecular Sciences, The University of Western Australia, Perth, WA 6009, Australia;
| | - Anton M. Jetten
- Cell Biology Section, Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA;
| | - Andrzej T. Slominski
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
- Laboratory Service of the VA Medical Center, Birmingham, AL 35294, USA
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Solanine Inhibits Immune Escape Mediated by Hepatoma Treg Cells via the TGF β/Smad Signaling Pathway. BIOMED RESEARCH INTERNATIONAL 2020; 2020:9749631. [PMID: 33204731 PMCID: PMC7655262 DOI: 10.1155/2020/9749631] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 09/05/2020] [Accepted: 10/15/2020] [Indexed: 01/14/2023]
Abstract
Objective To observe the inhibitory effect of solanine on regulatory T cells (Treg) in transplanted hepatoma mice and to study the mechanism of solanine inhibiting tumor growth. Methods The levels of Treg cells and IL-2, IL-10, and TGFβ in the blood of patients with liver cancer were detected by flow cytometry and ELISA, respectively. A mouse hepatocellular carcinoma (HCC) graft model was established and randomly divided into four groups: control group, solanine group, TGFβ inhibitor group (SB-431542), and solanine +TGFβ inhibitor combined group. Tumor volume of each group was recorded, tumor inhibition rate was calculated, and tumor metastasis was counted. The proportion of CD4+CD25+Foxp3+ Treg in transplanted tumor tissues was detected by flow cytometry. The expression levels of Foxp3 and TGFβ in transplanted tumor tissues were detected by quantitative fluorescence PCR. Results Compared with healthy people, Treg cells and IL-2, IL-10, and TGFβ contents in peripheral blood of liver cancer patients were increased. The results of the transplanted tumor model in mice showed that the tumor volume of the transplanted mice in the solanine group and the TGFβ inhibitor mice was reduced compared with the control group. The combined group had the smallest tumor volume. The proportion of CD4+CD25+Foxp3+ Treg in the transplanted tumor tissues of mice in the solanine treatment group was significantly lower than that in the control group. The expressions of Foxp3 and TGFβ in the transplanted tumor tissues of mice in the solanine group were significantly lower than those in the control group. Conclusion Solanine may enhance the antitumor immune response by downregulating the proportion of CD4+CD25+ Treg and the expression of Foxp3 and TGFβ in tumor tissues.
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Mei J, Xing Y, Lv J, Gu D, Pan J, Zhang Y, Liu J. Construction of an immune-related gene signature for prediction of prognosis in patients with cervical cancer. Int Immunopharmacol 2020; 88:106882. [PMID: 32799114 DOI: 10.1016/j.intimp.2020.106882] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 08/05/2020] [Accepted: 08/05/2020] [Indexed: 02/06/2023]
Abstract
Cervical cancer (CeCa) is becoming an intractable public health issue worldwide. Emerging evidence uncovers that the tumor progression and prognosis of patients with CeCa are tightly associated with the abundance of tumor-infiltrating immune cells. In the current study, the abundance of tumor-infiltrating immune cells in CeCa samples was assessed by using the ssGSEA, thereby generating two immune-related groups according to the immune status. A 4-gene prognostic signature (RIPOR2, DAAM2, SORBS1, and CXCL8) was next established based on the grouping and its predictive capability was validated by multiple analyses. The TIMER database was used to evaluate the association between 4 hub gene expression and immune cell infiltration. Immunophenoscore (IPS) was used to assess response to immune checkpoint inhibitors in CeCa samples. As the results, a novel grouping strategy based on immune cell infiltration was developed and validated. Based on the grouping, a 4-gene signature was identified to be an independent prognostic indicator for overall survival (OS) in CeCa patients. Among the 4 hub genes, RIPOR2 and CXCL8 expression were significantly correlated with immune cell infiltration. Besides, higher immune checkpoints expression and IPS scores were found in the 4-gene signature low-risk group, suggesting a more immunoactive status that tended to respond to immune checkpoint inhibitors. To sum up, a novel immune-related signature is established to predict CeCa patients' prognosis and also associated with response to immune checkpoint inhibitors, which might be a promising prognostic stratification strategy and innovate therapeutic management.
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Affiliation(s)
- Jie Mei
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi 214000, Jiangsu, China
| | - Yan Xing
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Jinru Lv
- Department of Emergency, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Dingyi Gu
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi 214000, Jiangsu, China
| | - Jiadong Pan
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi 214000, Jiangsu, China
| | - Yan Zhang
- Department of Gynecology and Obstetrics, Wuxi Maternal and Child Health Hospital, the Affiliated Hospital to Nanjing Medical University, Wuxi 214000, Jiangsu, China.
| | - Jinhui Liu
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.
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Husaini Y, Tsai VWW, Manandhar R, Zhang HP, Lee-Ng KKM, Lebhar H, Marquis CP, Brown DA, Breit SN. Growth differentiation factor-15 slows the growth of murine prostate cancer by stimulating tumor immunity. PLoS One 2020; 15:e0233846. [PMID: 32502202 PMCID: PMC7274405 DOI: 10.1371/journal.pone.0233846] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 05/13/2020] [Indexed: 02/07/2023] Open
Abstract
Growth Differentiation Factor-15 (GDF15) is a divergent TGF-beta superfamily cytokine that is overexpressed by most cancers and is induced by anticancer therapy. Transgenic and induced animal models suggest that it protects from cancer development but the mechanisms are uncertain. We investigated the role of immunity in GDF15 induced reduction in prostate cancer (PCa) growth. The C57BL/6 transgenic TRAMP prostate cancer prone mice were bred with mice that were immunodeficient and/or systemically overexpressed GDF15. We developed a novel orthotopic TRAMP PCa model in which primary TRAMP tumor cells were implanted into prostates of mice to reduce the study time. These mice were administered recombinant mouse GDF15, antibody to CD8, PD1 or their respective controls. We found that GDF15 induced protection from tumor growth was reversed by lack of adaptive immunity. Flow cytometric evaluation of lymphocytes within these orthotopic tumors showed that GDF15 overexpression was associated with increased CD8 T cell numbers and an increased number and proportion of recently activated CD8+CD11c+ T cells and a reduced proportion of "exhausted" CD8+PD1+ T cells. Further, depletion of CD8 T cells in tumor bearing mice abolished the GDF15 induced protection from tumor growth. Infusion of GDF15 into mice bearing orthotopic TRAMP tumor, substantially reduced tumor growth that was further reduced by concurrent PD1 antibody administration. GDF15 overexpression or recombinant protein protects from TRAMP tumor growth by modulating CD8 T cell mediated antitumor immunity and augments the positive effects of anti-PD1 blockers.
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Affiliation(s)
- Yasmin Husaini
- St Vincent’s Centre for Applied Medical Research, St Vincent’s Hospital and University of New South Wales, Sydney, New South Wales, Australia
| | - Vicky Wang-Wei Tsai
- St Vincent’s Centre for Applied Medical Research, St Vincent’s Hospital and University of New South Wales, Sydney, New South Wales, Australia
| | - Rakesh Manandhar
- St Vincent’s Centre for Applied Medical Research, St Vincent’s Hospital and University of New South Wales, Sydney, New South Wales, Australia
| | - Hong Ping Zhang
- St Vincent’s Centre for Applied Medical Research, St Vincent’s Hospital and University of New South Wales, Sydney, New South Wales, Australia
| | - Ka Ki Michelle Lee-Ng
- St Vincent’s Centre for Applied Medical Research, St Vincent’s Hospital and University of New South Wales, Sydney, New South Wales, Australia
| | - Hélène Lebhar
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia
| | - Christopher P. Marquis
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia
| | - David A. Brown
- St Vincent’s Centre for Applied Medical Research, St Vincent’s Hospital and University of New South Wales, Sydney, New South Wales, Australia
- The Institute for Pathology and Clinical Research, New South Wales Health Pathology and The Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Wesmead, New South Wales, Australia
| | - Samuel N. Breit
- St Vincent’s Centre for Applied Medical Research, St Vincent’s Hospital and University of New South Wales, Sydney, New South Wales, Australia
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Zhao X, Ning Q, Mo Z, Tang S. A promising cancer diagnosis and treatment strategy: targeted cancer therapy and imaging based on antibody fragment. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2020; 47:3621-3630. [PMID: 31468992 DOI: 10.1080/21691401.2019.1657875] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
With the arrival of the precision medicine and personalized treatment era, targeted therapy that improves efficacy and reduces side effects has become the mainstream approach of cancer treatment. Antibody fragments that further enhance penetration and retain the most critical antigen-specific binding functions are considered the focus of research targeting cancer imaging and therapy. Thanks to the superior penetration and rapid blood clearance of antibody fragments, antibody fragment-based imaging agents enable efficient and sensitive imaging of tumour sites. In tumour-targeted therapy, antibody fragments can directly inhibit tumour proliferation and growth, serve as an ideal carrier for delivery of anti-tumour drugs, or manipulate the immune system to eliminate tumour cells. In this review, the excellent physicochemical properties and the basic structure of antibody fragments are expressly depicted depicted, the progress of antibody fragments in cancer therapy and imaging are thoroughly summarized, and the future development of antibody fragments is predicted.
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Affiliation(s)
- Xuhong Zhao
- Learning Key Laboratory for Pharmacoproteomics of Hunan Province, Institute of Pharmacy and Pharmacology, University of South China , Hengyang , China.,Hunan Province Key Laboratory for Antibody-Based Drug and Intelligent Delivery System, Hunan University of Medicine , Huaihua , China
| | - Qian Ning
- Hunan Province Key Laboratory for Antibody-Based Drug and Intelligent Delivery System, Hunan University of Medicine , Huaihua , China
| | - Zhongcheng Mo
- Department of Histology and Embryology, Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China , Hengyang , China
| | - Shengsong Tang
- Learning Key Laboratory for Pharmacoproteomics of Hunan Province, Institute of Pharmacy and Pharmacology, University of South China , Hengyang , China.,Hunan Province Key Laboratory for Antibody-Based Drug and Intelligent Delivery System, Hunan University of Medicine , Huaihua , China
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The Vicious Cross-Talk between Tumor Cells with an EMT Phenotype and Cells of the Immune System. Cells 2019; 8:cells8050460. [PMID: 31096701 PMCID: PMC6562673 DOI: 10.3390/cells8050460] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 05/02/2019] [Accepted: 05/14/2019] [Indexed: 02/08/2023] Open
Abstract
Carcinoma cells that undergo an epithelial-mesenchymal transition (EMT) and display a predominantly mesenchymal phenotype (hereafter EMT tumor cells) are associated with immune exclusion and immune deviation in the tumor microenvironment (TME). A large body of evidence has shown that EMT tumor cells and immune cells can reciprocally influence each other, with EMT cells promoting immune exclusion and deviation and immune cells promoting, under certain circumstances, the induction of EMT in tumor cells. This cross-talk between EMT tumor cells and immune cells can occur both between EMT tumor cells and cells of either the native or adaptive immune system. In this article, we review this evidence and the functional consequences of it. We also discuss some recent evidence showing that tumor cells and cells of the immune system respond to similar stimuli, activate the expression of partially overlapping gene sets, and acquire, at least in part, identical functionalities such as migration and invasion. The possible significance of these symmetrical changes in the cross-talk between EMT tumor cells and immune cells is addressed. Eventually, we also discuss possible therapeutic opportunities that may derive from disrupting this cross-talk.
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Dong L, Zieren RC, Wang Y, de Reijke TM, Xue W, Pienta KJ. Recent advances in extracellular vesicle research for urological cancers: From technology to application. Biochim Biophys Acta Rev Cancer 2019; 1871:342-360. [DOI: 10.1016/j.bbcan.2019.01.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 01/28/2019] [Accepted: 01/28/2019] [Indexed: 02/09/2023]
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Meldolesi J. Extracellular vesicles, news about their role in immune cells: physiology, pathology and diseases. Clin Exp Immunol 2019; 196:318-327. [PMID: 30756386 DOI: 10.1111/cei.13274] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/30/2019] [Indexed: 12/11/2022] Open
Abstract
Two types of extracellular vesicles (EVs), exosomes and ectosomes, are generated and released by all cells, including immune cells. The two EVs appear different in many properties: size, mechanism and site of assembly, composition of their membranes and luminal cargoes, sites and processes of release. In functional terms, however, these differences are minor. Moreover, their binding to and effects on target cells appear similar, thus the two types are considered distinct only in a few cases, otherwise they are presented together as EVs. The EV physiology of the various immune cells differs as expected from their differential properties. Some properties, however, are common: EV release, taking place already at rest, is greatly increased upon cell stimulation; extracellular navigation occurs adjacent and at distance from the releasing cells; binding to and uptake by target cells are specific. EVs received from other immune or distinct cells govern many functions in target cells. Immune diseases in which EVs play multiple, often opposite (aggression and protection) effects, are numerous; inflammatory diseases; pathologies of various tissues; and brain diseases, such as multiple sclerosis. EVs also have effects on interactive immune and cancer cells. These effects are often distinct, promoting cytotoxicity or proliferation, the latter together with metastasis and angiogenesis. Diagnoses depend on the identification of EV biomarkers; therapies on various mechanisms such as (1) removal of aggression-inducing EVs; (2) EV manipulations specific for single targets, with insertion of surface peptides or luminal miRNAs; and (3) removal or re-expression of molecules from target cells.
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Affiliation(s)
- J Meldolesi
- Division of Neuroscience, Unit of Molecular and Cellular Neuroscience, San Raffaele Scientific Institute and San Raffaele University, Milan, Italy
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Son SH, Gangadaran P, Ahn BC. A novel strategy of transferring NIS protein to cells using extracellular vesicles leads to increase in iodine uptake and cytotoxicity. Int J Nanomedicine 2019; 14:1779-1787. [PMID: 30880979 PMCID: PMC6413815 DOI: 10.2147/ijn.s189738] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND This study was designed to explore a novel approach for transferring NIS protein to cells using extracellular vesicle (EV) and enhancing iodine avidity in hepatocellular carcinoma (HCC) cells. METHODS We transfected the HCC cells (Huh7) with NIS gene, designated as Huh7/NIS, and isolated the EVs from them. Presence of NIS protein in EVs and EV-mediated transport of NIS protein to recipient Huh7 cells were tested using Western blotting. We also examined radioiodine uptake in Huh7 cells treated with EV-Huh7/NIS. RESULTS Successful transfer of NIS protein into Huh7 cells was confirmed by WB and microscopy. EVs showed high levels of NIS protein in them. Treatment of Huh7 cells with EV-Huh7/NIS increased the NIS protein level and enhanced 125I uptake in recipient Huh7 cells. In addition, EV-huh7/NIS pre-treatment enhanced the cytotoxicity of 131I therapy against Huh7 cells by inducing increased DNA damage/increased γH2A.X foci formation. CONCLUSION This is the first-of-its-kind demonstration of successful transportation of the NIS protein to cells via EVs, which increased radioiodine uptake. This approach can revert radioiodine-resistant cancers into radioiodine-sensitive cancers.
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Affiliation(s)
- Seung Hyun Son
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea,
- Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea,
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea,
- Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea,
| | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea,
- Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea,
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Huang T, Deng CX. Current Progresses of Exosomes as Cancer Diagnostic and Prognostic Biomarkers. Int J Biol Sci 2019; 15:1-11. [PMID: 30662342 PMCID: PMC6329932 DOI: 10.7150/ijbs.27796] [Citation(s) in RCA: 176] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 10/15/2018] [Indexed: 12/23/2022] Open
Abstract
Cancer related exosomes are nano-size membrane vesicles that play important roles in tumor microenvironment. Emerging evidence indicates that exosomes can load unique cargoes, including proteins and nucleic acids that reflect the condition of tumor. Therefore, exosomes are being used as diagnostic and prognostic biomarkers for various cancers. In this review, we describe the current progresses of cancer related exosomes, including their biogenesis, molecular contents, biological functions, sources where they are derived from, and methods for their detection. We will also discuss the current exosomal biomarkers and the utilization of them for early diagnosis and prognostics in cancer.
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Affiliation(s)
| | - Chu-Xia Deng
- Faculty of Health Sciences, University of Macau, Macau SAR, China
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Dhillon VS, Yeoh E, Salisbury C, Butters J, Di Matteo A, Olver I, Fenech M. Cytokinesis Block Micronucleus Cytome (CBMN Cyt) Assay Biomarkers and Their Association With Radiation Sensitivity Phenotype in Prostate Cancer Cases and DNA Repair Gene hOGG1 (C1245G) Polymorphism. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2018; 59:813-821. [PMID: 30264500 DOI: 10.1002/em.22240] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 08/13/2018] [Accepted: 08/16/2018] [Indexed: 06/08/2023]
Abstract
Prostate cancer (PC) is commonly diagnosed cancer in men but only a few risk factors, such as family history, ethnicity, and age have been established. Chromosomal instability is another possible risk factor but this has not been adequately explained previously. In this study, we tested the hypotheses that peripheral blood lymphocytes (PBL) of PC patients have (1) an abnormally high level of chromosomal instability; (2) that they are hypersensitive to ionizing radiation-induced DNA damage; and (3) that these phenotypes are affected by hOGG1 (C1245G) polymorphism. These experiments were performed using the cytokinesis-block micronucleus Cytome (CBMN cyt) assay in PC cases and controls. We found that spontaneous or radiation-induced (3G) micronucleus (MN) frequency is not significantly different between both groups. However, spontaneous frequency of nucleoplasmic bridges (NPBs) and radiation-induced nuclear buds (NBuds) were significantly higher in patients vs. controls (P < 0.0001; P = 0.0005, respectively). In addition, apoptosis and nuclear division index (NDI) was significantly higher in patients compared to controls after radiation treatment (P = 0.006; P = 0.0002, respectively). Furthermore carriage of at least one G allele of hOGG1 (C1245G) polymorphism was associated with a significantly increased odds ratio (OR) to have a base-line MN, NPB, or NBud frequency greater than medium level compared to homozygotes for C allele (OR:1.94, 1.77, 2.36, respectively, P = 0.02; 0.04, and 0.004, respectively). Our results support the hypotheses that those who develop PC have significantly higher level of genomic instability which is further increased in those who carry G allele of the hOGG1 (C1245G) polymorphism. Environ. Mol. Mutagen. 59:813-821, 2018. © 2018 Wiley Periodicals, Inc.
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Affiliation(s)
| | - Eric Yeoh
- Department of Radiation Oncology, Royal Adelaide Hospital (RAH) and Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | | | - Julie Butters
- South Australian Health and Medical Research Institute, North Terrace, Adelaide, South Australia, Australia
| | - Addolorata Di Matteo
- Department of Radiation Oncology, Royal Adelaide Hospital (RAH) and Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Ian Olver
- Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia
| | - Michael Fenech
- School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia
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Köseoğlu H. Genetics in the Prostate Cancer. Prostate Cancer 2018. [DOI: 10.5772/intechopen.77259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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