|
1
|
Xiao Q, Tan M, Yan G, Peng L. Revolutionizing lung cancer treatment: harnessing exosomes as early diagnostic biomarkers, therapeutics and nano-delivery platforms. J Nanobiotechnology 2025; 23:232. [PMID: 40119368 PMCID: PMC11929271 DOI: 10.1186/s12951-025-03306-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 03/08/2025] [Indexed: 03/24/2025] Open
Abstract
Lung cancer, known for its high morbidity and mortality rates, remains one of the most critical health challenges globally. Conventional treatment options, such as chemotherapy and surgery, are often limited by high costs, significant side effects, and often yield a poor prognosis. Notably, recent research has shed light on the potential therapeutic roles of exosomes, which essentially influence lung cancer's development, diagnosis, treatment, and prognosis. Exosomes have been revealed for their exceptional properties, including natural intercellular communication, excellent biocompatibility, minimal toxicity, prolonged blood circulation ability, and biodegradability. These unique characteristics position exosomes as highly effective drug delivery systems, nanotherapeutics, and potential diagnostic and prognostic biomarkers in lung cancer. This review provides a comprehensive review of the physiological and pathological roles of exosomes in lung cancer, emphasizing their potential as innovative diagnostic biomarkers, therapeutics, and delivery platforms. By harnessing their unique properties, exosomes are poised to revolutionize the diagnosis and treatment of lung cancer, offering a promising avenue for more personalized and effective therapies.
Collapse
Affiliation(s)
- Qiyao Xiao
- College of Pharmaceutical Sciences, Zhejiang University, 866# Yuhangtang Road, Hangzhou, 310058, People's Republic of China
| | - Minhong Tan
- College of Pharmaceutical Sciences, Zhejiang University, 866# Yuhangtang Road, Hangzhou, 310058, People's Republic of China
| | - Ge Yan
- College of Pharmaceutical Sciences, Zhejiang University, 866# Yuhangtang Road, Hangzhou, 310058, People's Republic of China
| | - Lihua Peng
- College of Pharmaceutical Sciences, Zhejiang University, 866# Yuhangtang Road, Hangzhou, 310058, People's Republic of China.
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, People's Republic of China.
| |
Collapse
|
|
2
|
Wang F, Li L, Sun X, Cai X, Wang J, Luo H, Wang Y, Ni D, Wang D. The feedback loop between miR-222-3p and ZEB1 harnesses metastasis in renal cell carcinoma. Cell Death Discov 2025; 11:97. [PMID: 40074730 PMCID: PMC11903659 DOI: 10.1038/s41420-025-02385-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 02/12/2025] [Accepted: 03/03/2025] [Indexed: 03/14/2025] Open
Abstract
Renal cell carcinoma (RCC) is an aggressive malignancy originating from the renal parenchyma, often leading to high mortality due to local invasion and distant metastasis. MicroRNAs (miRNAs) play essential roles in RCC progression. Through miRNA sequencing, we identified significant upregulation of miR-222-3p in metastatic RCC tissues. Exosomes from highly metastatic RCC cells were found to transfer miR-222-3p to low-metastatic cells, enhancing their migration and invasion. Mechanistically, miR-222-3p directly targets the 3' untranslated region (3'UTR) of the tumor-suppressor TRPS1, reducing its expression. TRPS1 downregulation releases its inhibitory effect on ZEB1, a key regulator of epithelial-mesenchymal transition (EMT), thereby promoting EMT and metastatic traits. ZEB1 further transactivates miR-222-3p, establishing a positive feedback loop. Additionally, miR-222-3p promotes a pre-metastatic niche by inducing M2 macrophage polarization, facilitating distant metastasis. These findings highlight miR-222-3p as a critical driver of RCC metastasis and suggest its potential as a diagnostic marker and therapeutic target for RCC.
Collapse
Affiliation(s)
- Fan Wang
- Department of Thyroid and Breast Surgery, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, China
| | - Liao Li
- Department of Child Healthcare, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, China
| | - Xiangfu Sun
- Department of Cardiothoracic Surgery, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, China
| | - Xianfu Cai
- Department of Renal Transplantation, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Jianjun Wang
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Huiwen Luo
- NHC Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Yaodong Wang
- Department of Urology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Dong Ni
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Decai Wang
- Department of Urology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China.
| |
Collapse
|
|
3
|
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.
Collapse
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
| |
Collapse
|
|
4
|
Yu L, Guo Q, Li Y, Mao M, Liu Z, Li T, Wang L, Zhang X. CHMP4C promotes pancreatic cancer progression by inhibiting necroptosis via the RIPK1/RIPK3/MLKL pathway. J Adv Res 2025:S2090-1232(25)00058-X. [PMID: 39870301 DOI: 10.1016/j.jare.2025.01.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 01/10/2025] [Accepted: 01/24/2025] [Indexed: 01/29/2025] Open
Abstract
INTRODUCTION Pancreatic cancer (PC) cannot currently be completely cured and has a poor prognosis. Necroptosis is a distinct form of regulated cell death that differs from both necrosis and apoptosis. Understanding the role of necroptosis during PC progression would open new avenues for targeted therapy. OBJECTIVES The purpose of this study is to examine the impact of necroptosis on the progression of PC and related mechanisms. METHODS RNA sequencing was performed to identify necroptosis-related genes that are differentially expressed in PC tissues. The biological functions of CHMP4C and its necroptosis effects were determined in vitro and in vivo. RNA immunoprecipitation, MeRIP-qPCR, Co-immunoprecipitation assays were conducted to evaluate the interaction among CHMP4C, YBX1 and caspase-8 mRNA. Extracellular vesicles were isolated using the differential ultracentrifugation method. The expression of CHMP4C, p-MLKL and CD117 were detected on a PC tissue microarray using multiplex immunofluorescence staining. RESULTS CHMP4C was significantly overexpressed in PC cells and tissues. It promoted cell growth and suppressed necroptosis of PC cells in both in vivo and in vitro settings. Mechanistically, CHMP4C interacted with YBX1 to mediate m5C modification of caspase-8 mRNA, resulting in increased caspase-8 expression and inhibition of RIPK1/RIPK3/MLKL pathway phosphorylation. Furthermore, CHMP4C promoted extracellular exocytosis of p-MLKL to further suppress necroptosis. Additionally, PC cells used CHMP4C within extracellular vesicles to recruit and stimulate mast cells (MCs), which in turn promoted PC cell proliferation. In PC tissues, the expression of CHMP4C showed a negative correlation with p-MLKL and a positive association with CD117. High expression levels of CHMP4C in patients were associated with poorer overall survival outcomes. CONCLUSIONS CHMP4C promotes PC progression by inhibiting necroptosis, which has potential as a biomarker and therapeutic target in PC.
Collapse
Affiliation(s)
- Longchen Yu
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012 China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012 China
| | - Qining Guo
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012 China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012 China
| | - Yaping Li
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012 China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012 China
| | - Mai Mao
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012 China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012 China
| | - Zhenping Liu
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012 China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012 China
| | - Tingting Li
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012 China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012 China
| | - Lei Wang
- Department of Orthodontics, Qilu Hospital of Shandong University, Jinan 250012 China.
| | - Xin Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012 China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012 China.
| |
Collapse
|
|
5
|
Huang X, Tang Y. Unveiling the complex double-edged sword role of exosomes in nasopharyngeal carcinoma. PeerJ 2025; 13:e18783. [PMID: 39822977 PMCID: PMC11737332 DOI: 10.7717/peerj.18783] [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: 09/17/2024] [Accepted: 12/09/2024] [Indexed: 01/19/2025] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a malignancy arising from the epithelium of the nasopharynx. Given its late diagnosis, NPC raises serious considerations in Southeast Asia. In addition to resistance to conventional treatment that combines chemotherapy and radiation, NPC has high rates of metastasis and frequent recurrence. Exosomes are small membrane vesicles at the nanoscale that transport physiologically active compounds from their source cell and have a crucial function in signal transmission and intercellular message exchange. The exosomes detected in the tissues of NPC patients have recently emerged as a potential non-invasive liquid biopsy biomarker that plays a role in controlling the tumor pathophysiology. Here, we take a look back at what we know so far about the complex double-edged sword role of exosomes in NPC. Exosomes could serve as biomarkers and therapeutic agents, as well as the molecular mechanisms by which they promote cell growth, angiogenesis, metastasis, immunosuppression, radiation resistance, and chemotherapy resistance in NPC. Furthermore, we go over some of the difficulties and restrictions associated with exosome use. It is anticipated that this article would provide the reference for the apply of exosomes in clinical practice.
Collapse
Affiliation(s)
- Xueyan Huang
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Yuedi Tang
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, China
| |
Collapse
|
|
6
|
Liu J, Zhang B, Huang B, Zhang K, Guo F, Wang Z, Shang D. A stumbling block in pancreatic cancer treatment: drug resistance signaling networks. Front Cell Dev Biol 2025; 12:1462808. [PMID: 39872846 PMCID: PMC11770040 DOI: 10.3389/fcell.2024.1462808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 12/30/2024] [Indexed: 01/30/2025] Open
Abstract
The primary node molecules in the cell signaling network in cancer tissues are maladjusted and mutated in comparison to normal tissues, which promotes the occurrence and progression of cancer. Pancreatic cancer (PC) is a highly fatal cancer with increasing incidence and low five-year survival rates. Currently, there are several therapies that target cell signaling networks in PC. However, PC is a "cold tumor" with a unique immunosuppressive tumor microenvironment (poor effector T cell infiltration, low antigen specificity), and targeting a single gene or pathway is basically ineffective in clinical practice. Targeted matrix therapy, targeted metabolic therapy, targeted mutant gene therapy, immunosuppressive therapy, cancer vaccines, and other emerging therapies have shown great therapeutic potential, but results have been disappointing. Therefore, we summarize the identified and potential drug-resistant cell signaling networks aimed at overcoming barriers to existing PC therapies.
Collapse
Affiliation(s)
- Jinming Liu
- Department of General Surgery, Pancreas and Biliary Center, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Biao Zhang
- Department of General Surgery, Pancreas and Biliary Center, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Bingqian Huang
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Department of Clinical Pharmacy, Affiliated Hangzhou First People’s Hospital, Westlake University, Hangzhou, China
| | - Kexin Zhang
- Central Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Fujia Guo
- Central Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhizhou Wang
- Department of General Surgery, Pancreas and Biliary Center, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Dong Shang
- Department of General Surgery, Pancreas and Biliary Center, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| |
Collapse
|
|
7
|
Luan X, Wang X, Bian G, Li X, Gao Z, Liu Z, Zhang Z, Han T, Zhao J, Zhao H, Luan X, Zhu W, Dong L, Guo F. Exosome applications for the diagnosis and treatment of pancreatic ductal adenocarcinoma: An update (Review). Oncol Rep 2025; 53:13. [PMID: 39575479 PMCID: PMC11605277 DOI: 10.3892/or.2024.8846] [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: 08/08/2024] [Accepted: 10/30/2024] [Indexed: 11/28/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a malignant neoplasm that typically manifests with subtle clinical manifestations in its early stages and frequently eludes diagnosis until the advanced phases of the disease. The limited therapeutic options available for PDAC significantly contribute to its high mortality rate, highlighting the urgent need for novel biomarkers capable of effectively identifying early clinical manifestations and facilitating precise diagnosis. The pivotal role of cellular exosomes in both the pathogenesis and therapeutic interventions for PDAC has been underscored. Furthermore, researchers have acknowledged the potential of exosomes as targeted drug carriers against regulatory cells in treating PDAC. The present article aims to provide a comprehensive review encompassing recent advancements in utilizing exosomes for elucidating mechanisms underlying disease development, patterns of metastasis, diagnostic techniques and treatment strategies associated with PDAC.
Collapse
Affiliation(s)
- Xinchi Luan
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Xuezhe Wang
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Gang Bian
- Department of Gastroenterology, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, Shandong 266041, P.R. China
| | - Xiaoxuan Li
- Department of Oncology, Key Laboratory of Cancer Molecular and Translational Research, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266031, P.R. China
| | - Ziru Gao
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Zijiao Liu
- School of Clinical and Basic Medicine and Institute of Basic Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
| | - Zhishang Zhang
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Tianyue Han
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Jinpeng Zhao
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Hongjiao Zhao
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Xinyue Luan
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Wuhui Zhu
- Department of Hepatobiliary surgery, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, Shandong 266041, P.R. China
| | - Lili Dong
- Department of Gastroenterology, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, Shandong 266041, P.R. China
| | - Feifei Guo
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| |
Collapse
|
|
8
|
Li TY, Qin C, Zhao BB, Li ZR, Wang YY, Zhao YT, Wang WB. Construction of a prognostic model with exosome biogenesis- and release-related genes and identification of RAB27B in immune infiltration of pancreatic cancer. Transl Cancer Res 2024; 13:4846-4865. [PMID: 39430819 PMCID: PMC11483359 DOI: 10.21037/tcr-24-54] [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: 01/09/2024] [Accepted: 07/19/2024] [Indexed: 10/22/2024]
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and fatal disease. Exosomes are extracellular vesicles that plays a vital rule in the progression and metastasis of PDAC. However, the specific mechanism of exosome biogenesis and release in the tumorigenesis and development of pancreatic cancer remains elusive. The aim of this study is to develop novel biomarkers and construct a reliable prognostic signature to accurately stratify patients and optimize clinical decision-making. Methods Gene expression and clinical data were acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Univariate Cox regression analysis, random forest analysis, least absolute shrinkage and selection operator (LASSO) regression analysis, and multivariate Cox regression analysis were used to construct the risk signature. The effectiveness of the model was validated by survival point plot, Kaplan-Meier survival analysis, and receiver operating characteristic (ROC) curve in training, testing and entire cohorts. Meanwhile, single sample gene set enrichment analysis (ssGSEA), ESTIMATE and CIBERSORT algorithm were utilized to assess the association of the risk signature with the immune status in the PDAC tumor microenvironment. We also performed functional enrichment, tumor mutation analysis, and DNA methylation analyses based on the risk signature. The function of the core gene was further verified by polymerase chain reaction (PCR), western blot, bicinchoninic acid (BCA), immunohistochemistry (IHC) and in vitro experiments including cell proliferation, migration, and apoptosis experiments. Results We constructed an exosome biogenesis- and release-related risk model which could serve as an effective and independent prognosis predictor for PDAC patients. The immune infiltration analysis revealed that our signature was related to the PDAC immune microenvironment, mainly associated with a lower proportion of natural killer (NK) cells and CD8+ T cells. Tissue microarray IHC confirmed the association of RAB27B with poor prognosis in PDAC. Knockdown of RAB27B expression promoted PDAC cells' apoptosis, while decreased cellular proliferation and migration. Also, knockdown of RAB27B expression led to reduced exosome secretion, while RAB27B overexpression promoted exosome secretion. Conclusions The predictive signature can predict overall survival, help elucidate the mechanism of exosome biogenesis and release, and provide immunotherapy guidance for PDAC patients.
Collapse
Affiliation(s)
- Tian-Yu Li
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, China
| | - Cheng Qin
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, China
| | - Bang-Bo Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, China
| | - Ze-Ru Li
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, China
| | - Yuan-Yang Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, China
| | - Yu-Tong Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, China
| | - Wei-Bin Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, China
| |
Collapse
|
|
9
|
Xu D, Jia M, Yang F, Zhang X, Jiang K. Analyzing the role of TM4SF1 expression in pancreatic adenocarcinoma: understanding prognostic implications and therapeutic opportunities. J Gastrointest Oncol 2024; 15:1760-1776. [PMID: 39279979 PMCID: PMC11399867 DOI: 10.21037/jgo-24-564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 08/17/2024] [Indexed: 09/18/2024] Open
Abstract
Background Pancreatic adenocarcinoma (PAAD) is a highly lethal malignancy characterized by aggressive growth and poor prognosis. Understanding the molecular mechanisms underlying PAAD is crucial for developing effective therapies. This study aimed to explore the role of TM4SF1 and other key genes in PAAD progression, their prognostic implications, and therapeutic opportunities. Methods Differential gene expression analysis was performed using PAAD and normal tissue samples to identify upregulated genes, with TM4SF1 emerging as significantly elevated in PAAD. Functional enrichment analysis elucidated associated signaling pathways. A prognostic model comprising BPIFB4, PLEKHN1, CPTP, DVL1, and DDR1 was developed using least absolute shrinkage and selection operator (LASSO) regression and validated in an independent cohort. Genetic mutation analysis provided insights into the functional significance of identified genes. Pharmacogenomic analysis examined associations between gene expression and drug sensitivity. Experimental validation included quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot analyses to confirm gene expression patterns and protein levels. Results Lower TM4SF1 expression correlated with enhanced anti-tumor immune activity in PAAD, suggesting a complex interplay between genetic expression and immune response. The prognostic model showed robust associations with patient survival outcomes, validated across diverse patient cohorts. Genetic mutation analysis highlighted potential therapeutic targets. Pharmacogenomic analysis revealed correlations between gene expression profiles and drug responsiveness, suggesting personalized treatment strategies. Experimental validation confirmed elevated TM4SF1 levels in tumor tissues and demonstrated its role in promoting cancer cell proliferation and colony formation. Conclusions This study advances understanding of the molecular landscape of PAAD, emphasizing TM4SF1 as a key regulator and potential therapeutic target. The integration of genetic expression, immune response dynamics, and pharmacogenomics offers a multifaceted approach to personalized treatment strategies for PAAD, paving the way for improved patient outcomes and novel therapeutic interventions. Further research is warranted to elucidate the clinical utility of targeting TM4SF1 and other identified genes in PAAD management.
Collapse
Affiliation(s)
- Dong Xu
- Pancreas Center & Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of General Surgery, Gaochun People's Hospital, Nanjing, China
| | - Mingguang Jia
- Department of General Surgery, Zibo Municipal Hospital, Zibo, China
| | - Fei Yang
- Department of General Surgery, Gaochun People's Hospital, Nanjing, China
| | - Xiaohui Zhang
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Kuirong Jiang
- Pancreas Center & Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
10
|
Saczuk K, Dudek M, Matczyszyn K, Deiana M. Advancements in molecular disassembly of optical probes: a paradigm shift in sensing, bioimaging, and therapeutics. NANOSCALE HORIZONS 2024; 9:1390-1416. [PMID: 38963132 DOI: 10.1039/d4nh00186a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/05/2024]
Abstract
The majority of self-assembled fluorescent dyes suffer from aggregation-caused quenching (ACQ), which detrimentally affects their diagnostic and therapeutic effectiveness. While aggregation-induced emission (AIE) active dyes offer a promising solution to overcome this limitation, they may face significant challenges as the intracellular environment often prevents aggregation, leading to disassembly and posing challenges for AIE fluorogens. Recent progress in signal amplification through the disassembly of ACQ dyes has opened new avenues for creating ultrasensitive optical sensors and enhancing phototherapeutic outcomes. These advances are well-aligned with cutting-edge technologies such as single-molecule microscopy and targeted molecular therapies. This work explores the concept of disaggregation-induced emission (DIE), showcasing the revolutionary capabilities of DIE-based dyes from their design to their application in sensing, bioimaging, disease monitoring, and treatment in both cellular and animal models. Our objective is to provide an in-depth comparison of aggregation versus disaggregation mechanisms, aiming to stimulate further advancements in the design and utilization of ACQ fluorescent dyes through DIE technology. This initiative is poised to catalyze scientific progress across a broad spectrum of disciplines.
Collapse
Affiliation(s)
- Karolina Saczuk
- Institute of Advanced Materials, Faculty of Chemistry, Wrocław University of Science and Technology, 50-370 Wrocław, Poland.
| | - Marta Dudek
- Institute of Advanced Materials, Faculty of Chemistry, Wrocław University of Science and Technology, 50-370 Wrocław, Poland.
| | - Katarzyna Matczyszyn
- Institute of Advanced Materials, Faculty of Chemistry, Wrocław University of Science and Technology, 50-370 Wrocław, Poland.
- International Institute for Sustainability with Knotted Chiral Meta Matter (WPI-SKCM(2)), Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8526, Japan
| | - Marco Deiana
- Institute of Advanced Materials, Faculty of Chemistry, Wrocław University of Science and Technology, 50-370 Wrocław, Poland.
| |
Collapse
|
|
11
|
Wei C, Zhang C, Zhou Y, Wang J, Jin Y. Progress of Exosomal LncRNAs in Pancreatic Cancer. Int J Mol Sci 2024; 25:8665. [PMID: 39201351 PMCID: PMC11354448 DOI: 10.3390/ijms25168665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 07/27/2024] [Accepted: 07/28/2024] [Indexed: 09/02/2024] Open
Abstract
Pancreatic cancer is a prevalent malignant tumor with rising medication resistance and mortality. Due to a dearth of specific and trustworthy biomarkers and therapeutic targets, pancreatic cancer early detection and treatment are still not at their best. Exosomal LncRNAs have been found to be plentiful and persistent within exosomes, and they are capable of functioning whether the exosomes are traveling to close or distant cells. Furthermore, increasing evidence suggests that exosomal LncRNA, identified as an oncogene or tumor suppressor-control the growth, metastasis, and susceptibility of pancreatic cancer to chemotherapy and radiation therapy. Promising prospects for both antitumor targets and diagnostic biomarkers are exosomal LncRNAs. The primary features of exosomal LncRNAs, their biological roles in the onset and progression of pancreatic cancer, and their potential as therapeutic targets and diagnostic molecular markers are outlined in this review.
Collapse
Affiliation(s)
| | | | | | | | - Yong Jin
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
| |
Collapse
|
|
12
|
Cao Y, Xing R, Yang F, Zhang Y, Zhou X. Establishment of a prognostic model for pancreatic cancer based on vesicle-mediated transport protein-related genes. Comput Methods Biomech Biomed Engin 2024:1-11. [PMID: 38967327 DOI: 10.1080/10255842.2024.2367739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 06/06/2024] [Indexed: 07/06/2024]
Abstract
This study attempted to build a prognostic riskscore model for pancreatic cancer (PC) patients based on vesicle-mediated transport protein-related genes (VMTGs). We initially conducted differential expression analysis and Cox regression analysis, followed by the construction of a riskscore model to classify PC patients into high-risk (HR) and low-risk (LR) groups. The GEO GSE62452 dataset further validated the model. Kaplan-Meier survival analysis was employed to analyze the survival rate of the HR group and LR group. Cox analysis confirmed the independent prognostic ability of the riskscore model. Additionally, we evaluated immune status in both HR and LR groups, utilizing data from the GDSC database to predict drug response among PC patients. We identified six PC-specific genes from 724 VMTGs. Survival analysis revealed that the survival rate of the HR group was lower than that of the LR group (P<0.05). Cox analysis confirmed that the prognostic riskscore model could independently predict the survival status of PC patients (P<0.001). Immunological analysis revealed that the ESTIMATE score, immune score, and stroma score of the HR group were considerably lower than those of the LR group, and the tumor purity score of the HR group was higher. The IC50 values of Gemcitabine, Irinotecan, Oxaliplatin, and Paclitaxel in the LR group were considerably lower than those in the HR group (P<0.001). In summary, the VMTG-based prognostic riskscore model could stratify PC risk and effectively predict the survival of PC patients.
Collapse
Affiliation(s)
- Yanfang Cao
- Department of Gastroenterology, Taizhou Municipal Hospital, Taizhou City, Zhejiang Province, China
| | - Renwei Xing
- Department of Hepatobiliary Surgery, Taizhou Municipal Hospital, Taizhou City, Zhejiang Province, China
| | - Fan Yang
- Department of Hepatobiliary Surgery, Taizhou Municipal Hospital, Taizhou City, Zhejiang Province, China
| | - Yang Zhang
- Department of Hepatobiliary Surgery, Taizhou Municipal Hospital, Taizhou City, Zhejiang Province, China
| | - Xianfei Zhou
- Department of Hepatobiliary Surgery, Taizhou Municipal Hospital, Taizhou City, Zhejiang Province, China
| |
Collapse
|
|
13
|
Chen Y, Kleeff J, Sunami Y. Pancreatic cancer cell- and cancer-associated fibroblast-derived exosomes in disease progression, metastasis, and therapy. Discov Oncol 2024; 15:253. [PMID: 38954230 PMCID: PMC11220035 DOI: 10.1007/s12672-024-01111-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 06/19/2024] [Indexed: 07/04/2024] Open
Abstract
Exosomes play a crucial role in the progression and spread of pancreatic cancer, serving not only as promoters of tumor growth and organ-specific metastasis but also as promising biomarkers and targets for treatment. These nano vesicles enhance intercellular communication by transferring bioactive molecules, such as proteins and RNAs, between cells. This process significantly affects cancer cell dynamics, including their proliferation, migration, and invasion, while also contributing to drug resistance. Our review focuses on the crucial interactions between cancer cells and fibroblasts mediated by exosomes within the pancreatic cancer microenvironment. We delve into how exosomes from both cancer-associated fibroblasts and the cancer cells themselves drive tumor progression through various mechanisms, such as epithelial-mesenchymal transition and facilitating metastasis to specific organs like the lungs and liver. The potential of leveraging exosomes for therapeutic interventions is also explored, highlighting the importance of understanding their role in cell communication as a step forward in developing more effective pancreatic cancer treatments.
Collapse
Affiliation(s)
- Yijun Chen
- Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, University Medical Center Halle, Ernst-Grube-Str. 40, 06120, Halle (Saale), Germany
| | - Jörg Kleeff
- Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, University Medical Center Halle, Ernst-Grube-Str. 40, 06120, Halle (Saale), Germany
| | - Yoshiaki Sunami
- Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, University Medical Center Halle, Ernst-Grube-Str. 40, 06120, Halle (Saale), Germany.
| |
Collapse
|
|
14
|
Cordeiro HG, Azevedo-Martins JM, Faria AVDS, Rocha-Brito KJP, Milani R, Peppelenbosch M, Fuhler G, de Fátima Â, Ferreira-Halder CV. Calix[6]arene dismantles extracellular vesicle biogenesis and metalloproteinases that support pancreatic cancer hallmarks. Cell Signal 2024; 119:111174. [PMID: 38604340 DOI: 10.1016/j.cellsig.2024.111174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 04/01/2024] [Accepted: 04/09/2024] [Indexed: 04/13/2024]
Abstract
Many challenges are faced in pancreatic cancer treatment due to late diagnosis and poor prognosis because of high recurrence and metastasis. Extracellular vesicles (EVs) and matrix metalloproteinases (MMPs), besides acting in intercellular communication, are key players in the cancer cell plasticity responsible for initiating metastasis. Therefore, these entities provide valuable targets for the development of better treatments. In this context, this study aimed to evaluate the potential of calix[6]arene to disturb the release of EVs and the activity of MMPs in pancreatic cancer cells. We found a correlation between the endocytic-associated mediators and the prognosis of pancreatic cancer patients. We observed a more active EV machinery in the pancreatic cancer cell line PANC-1, which was reduced three-fold by treatment with calix[6]arene at subtoxic concentration (5 μM; p 〈0,001). We observed the modulation of 186 microRNAs (164 miRNAs upregulated and 22 miRNAs downregulated) upon calix[6]arene treatment. Interestingly, some of them as miR-4443 and miR-3909, regulates genes HIF1A e KIF13A that are well known to play a role in transport of vesicles. Furthermore, Calix[6]arene downmodulated matrix metalloproteinases (MMPs) -2 and - 9 and disturbed the viability of pancreatic organoids which recapitulate the cellular heterogeneity, structure, and functions of primary tissues. Our findings shed new insights on calix[6]arene's antitumor mechanism, including its intracellular effects on vesicle production and trafficking, as well as MMP activity, which may harm the tumor microenvironment and contribute to a reduction in cancer cell dissemination, which is one of the challenges associated with high mortality in pancreatic cancer.
Collapse
Affiliation(s)
- Helon Guimarães Cordeiro
- Department of Biochemistry and Tissue Biology, Institute of Biology, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Jordana Maria Azevedo-Martins
- Department of Biochemistry and Tissue Biology, Institute of Biology, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Alessandra Valéria de Sousa Faria
- Department of Biochemistry and Tissue Biology, Institute of Biology, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil; Faculdade Israelita de Ciências da Saúde Albert Einstein, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | | | - Renato Milani
- Department of Biochemistry and Tissue Biology, Institute of Biology, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Maikel Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Gwenny Fuhler
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Ângelo de Fátima
- Department of Chemistry, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Carmen Veríssima Ferreira-Halder
- Department of Biochemistry and Tissue Biology, Institute of Biology, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil.
| |
Collapse
|
|
15
|
Wang Z, Dong S, Zhou W. Pancreatic stellate cells: Key players in pancreatic health and diseases (Review). Mol Med Rep 2024; 30:109. [PMID: 38695254 PMCID: PMC11082724 DOI: 10.3892/mmr.2024.13233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 04/09/2024] [Indexed: 05/12/2024] Open
Abstract
As a pluripotent cell, activated pancreatic stellate cells (PSCs) can differentiate into various pancreatic parenchymal cells and participate in the secretion of extracellular matrix and the repair of pancreatic damage. Additionally, PSCs characteristics allow them to contribute to pancreatic inflammation and carcinogenesis. Moreover, a detailed study of the pathogenesis of activated PSCs in pancreatic disease can offer promise for the development of innovative therapeutic strategies and improved patient prognoses. Therefore, the present study review aimed to examine the involvement of activated PSCs in pancreatic diseases and elucidate the underlying mechanisms to provide a viable therapeutic strategy for the management of pancreas‑related diseases.
Collapse
Affiliation(s)
- Zhengfeng Wang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Shi Dong
- The Second School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Wence Zhou
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730000, P.R. China
| |
Collapse
|
|
16
|
Jin X, Zhang J, Zhang Y, He J, Wang M, Hei Y, Guo S, Xu X, Liu Y. Different origin-derived exosomes and their clinical advantages in cancer therapy. Front Immunol 2024; 15:1401852. [PMID: 38994350 PMCID: PMC11236555 DOI: 10.3389/fimmu.2024.1401852] [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: 03/16/2024] [Accepted: 06/13/2024] [Indexed: 07/13/2024] Open
Abstract
Exosomes, as a class of small extracellular vesicles closely related to the biological behavior of various types of tumors, are currently attracting research attention in cancer diagnosis and treatment. Regarding cancer diagnosis, the stability of their membrane structure and their wide distribution in body fluids render exosomes promising biomarkers. It is expected that exosome-based liquid biopsy will become an important tool for tumor diagnosis in the future. For cancer treatment, exosomes, as the "golden communicators" between cells, can be designed to deliver different drugs, aiming to achieve low-toxicity and low-immunogenicity targeted delivery. Signaling pathways related to exosome contents can also be used for safer and more effective immunotherapy against tumors. Exosomes are derived from a wide range of sources, and exhibit different biological characteristics as well as clinical application advantages in different cancer therapies. In this review, we analyzed the main sources of exosomes that have great potential and broad prospects in cancer diagnosis and therapy. Moreover, we compared their therapeutic advantages, providing new ideas for the clinical application of exosomes.
Collapse
Affiliation(s)
- Xiaoyan Jin
- Department of Cell Biology and Genetics, Medical College of Yan’an University, Yan’an, Shaanxi, China
| | - Jing Zhang
- Department of Cell Biology and Genetics, Medical College of Yan’an University, Yan’an, Shaanxi, China
- The Second Affiliated Hospital of Xi‘an Medical University, Xi’an, Shaanxi, China
| | - Yufu Zhang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Yan’an University, Yan’an, Shaanxi, China
| | - Jing He
- Laboratory of Obstetrics and Gynecology, The Affiliated Hospital of Yan’an University, Yan’an, Shaanxi, China
| | - Mingming Wang
- Department of Cell Biology and Genetics, Medical College of Yan’an University, Yan’an, Shaanxi, China
| | - Yu Hei
- Department of Cell Biology and Genetics, Medical College of Yan’an University, Yan’an, Shaanxi, China
| | - Shutong Guo
- Department of Cell Biology and Genetics, Medical College of Yan’an University, Yan’an, Shaanxi, China
| | - Xiangrong Xu
- Department of Cell Biology and Genetics, Medical College of Yan’an University, Yan’an, Shaanxi, China
| | - Yusi Liu
- Department of Cell Biology and Genetics, Medical College of Yan’an University, Yan’an, Shaanxi, China
| |
Collapse
|
|
17
|
Zhang W, Song M, Fang Z, Chen F, Yuan H, Gao X, Liu K. Role of extracellular vesicles in insulin resistance: Signaling pathways, bioactive substances, miRNAs, and therapeutic potential. Cell Biochem Funct 2024; 42:e4013. [PMID: 38639198 DOI: 10.1002/cbf.4013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 03/31/2024] [Accepted: 04/03/2024] [Indexed: 04/20/2024]
Abstract
Extracellular vesicles are small lipid bilayer particles that resemble the structure of cells and range in size from 30 to 1000 nm. They transport a variety of physiologically active molecules, such as proteins, lipids, and miRNAs. Insulin resistance (IR) is a pathological disease in which insulin-responsive organs or components become less sensitive to insulin's physiological effects, resulting in decreased glucose metabolism in target organs such as the liver, muscle, and adipose tissue. Extracellular vesicles have received a lot of attention as essential intercellular communication mediators in the setting of IR. This review looks at extracellular vesicles' role in IR from three angles: signaling pathways, bioactive compounds, and miRNAs. Relevant publications are gathered to investigate the induction, inhibition, and bidirectional regulation of extracellular vesicles in IR, as well as their role in insulin-related illnesses. Furthermore, considering the critical function of extracellular vesicles in regulating IR, the study analyzes the practicality of employing extracellular vesicles for medication delivery and the promise of combination therapy for IR.
Collapse
Affiliation(s)
- Wang Zhang
- College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Mengdi Song
- College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Zhou Fang
- College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Feng Chen
- College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Hui Yuan
- College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Xinran Gao
- College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Kehai Liu
- College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
- Marine Biomedical Science and Technology Innovation Platform of Lin-gang Special Area, Shanghai, China
| |
Collapse
|
|
18
|
Chak PT, Kam NW, Choi TH, Dai W, Kwong DLW. Unfolding the Complexity of Exosome-Cellular Interactions on Tumour Immunity and Their Clinical Prospects in Nasopharyngeal Carcinoma. Cancers (Basel) 2024; 16:919. [PMID: 38473281 DOI: 10.3390/cancers16050919] [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: 01/26/2024] [Revised: 02/19/2024] [Accepted: 02/23/2024] [Indexed: 03/14/2024] Open
Abstract
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy situated in the posterolateral nasopharynx. NPC poses grave concerns in Southeast Asia due to its late diagnosis. Together with resistance to standard treatment combining chemo- and radiotherapy, NPC presents high metastatic rates and common recurrence. Despite advancements in immune-checkpoint inhibitors (ICIs) and cytotoxic-T-lymphocytes (CTLs)-based cellular therapy, the exhaustive T cell profile and other signs of immunosuppression within the NPC tumour microenvironment (TME) remain as concerns to immunotherapy response. Exosomes, extracellular vesicles of 30-150 nm in diameter, are increasingly studied and linked to tumourigenesis in oncology. These bilipid-membrane-bound vesicles are packaged with a variety of signalling molecules, mediating cell-cell communications. Within the TME, exosomes can originate from tumour, immune, or stromal cells. Although there are studies on tumour-derived exosomes (TEX) in NPC and their effects on tumour processes like angiogenesis, metastasis, therapeutic resistance, there is a lack of research on their involvement in immune evasion. In this review, we aim to enhance the comprehension of how NPC TEX contribute to cellular immunosuppression. Furthermore, considering the detectability of TEX in bodily fluids, we will also discuss the potential development of TEX-related biomarkers for liquid biopsy in NPC as this could facilitate early diagnosis and prognostication of the disease.
Collapse
Affiliation(s)
- Paak-Ting Chak
- Department of Clinical Oncology, Centre of Cancer Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
| | - Ngar-Woon Kam
- Department of Clinical Oncology, Centre of Cancer Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
- Laboratory for Synthetic Chemistry and Chemical Biology Limited, Hong Kong Science Park, New Territories, Hong Kong 999077, China
| | - Tsz-Ho Choi
- Department of Clinical Oncology, Centre of Cancer Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
| | - Wei Dai
- Department of Clinical Oncology, Centre of Cancer Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
- Clinical Oncology Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
| | - Dora Lai-Wan Kwong
- Department of Clinical Oncology, Centre of Cancer Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
- Clinical Oncology Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
| |
Collapse
|
|
19
|
Mendes I, Vale N. Overcoming Microbiome-Acquired Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma. Biomedicines 2024; 12:227. [PMID: 38275398 PMCID: PMC10813061 DOI: 10.3390/biomedicines12010227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 01/13/2024] [Accepted: 01/17/2024] [Indexed: 01/27/2024] Open
Abstract
Gastrointestinal cancers (GICs) are one of the most recurrent diseases in the world. Among all GICs, pancreatic cancer (PC) is one of the deadliest and continues to disrupt people's lives worldwide. The most frequent pancreatic cancer type is pancreatic ductal adenocarcinoma (PDAC), representing 90 to 95% of all pancreatic malignancies. PC is one of the cancers with the worst prognoses due to its non-specific symptoms that lead to a late diagnosis, but also due to the high resistance it develops to anticancer drugs. Gemcitabine is a standard treatment option for PDAC, however, resistance to this anticancer drug develops very fast. The microbiome was recently classified as a cancer hallmark and has emerged in several studies detailing how it promotes drug resistance. However, this area of study still has seen very little development, and more answers will help in developing personalized medicine. PC is one of the cancers with the highest mortality rates; therefore, it is crucial to explore how the microbiome may mold the response to reference drugs used in PDAC, such as gemcitabine. In this article, we provide a review of what has already been investigated regarding the impact that the microbiome has on the development of PDAC in terms of its effect on the gemcitabine pathway, which may influence the response to gemcitabine. Therapeutic advances in this type of GIC could bring innovative solutions and more effective therapeutic strategies for other types of GIC, such as colorectal cancer (CRC), due to its close relation with the microbiome.
Collapse
Affiliation(s)
- Inês Mendes
- PerMed Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal;
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
- School of Life and Environmental Sciences, University of Trás-os-Montes and Alto Douro (UTAD), Edifício de Geociências, 5000-801 Vila Real, Portugal
| | - Nuno Vale
- PerMed Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal;
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
- Department of Community Medicine, Information and Health Decision Sciences (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
| |
Collapse
|
|
20
|
Cafolla C, Philpott-Robson J, Elbourne A, Voïtchovsky K. Quantitative Detection of Biological Nanovesicles in Drops of Saliva Using Microcantilevers. ACS APPLIED MATERIALS & INTERFACES 2024; 16:44-53. [PMID: 38157306 PMCID: PMC10788824 DOI: 10.1021/acsami.3c12035] [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: 08/14/2023] [Revised: 12/06/2023] [Accepted: 12/07/2023] [Indexed: 01/03/2024]
Abstract
Extracellular nanovesicles (EVs) are lipid-based vesicles secreted by cells and are present in all bodily fluids. They play a central role in communication between distant cells and have been proposed as potential indicators for the early detection of a wide range of diseases, including different types of cancer. However, reliable quantification of a specific subpopulation of EVs remains challenging. The process is typically lengthy and costly and requires purification of relatively large quantities of biopsy samples. Here, we show that microcantilevers operated with sufficiently small vibration amplitudes can successfully quantify a specific subpopulation of EVs directly from a drop (0.1 mL) of unprocessed saliva in less than 20 min. Being a complex fluid, saliva is highly non-Newtonian, normally precluding mechanical sensing. With a combination of standard rheology and microrheology, we demonstrate that the non-Newtonian properties are scale-dependent, enabling microcantilever measurements with a sensitivity identical to that in pure water when operating at the nanoscale. We also address the problem of unwanted sensor biofouling by using a zwitterionic coating, allowing efficient quantification of EVs at concentrations down to 0.1 μg/mL, based on immunorecognition of the EVs' surface proteins. We benchmark the technique on model EVs and illustrate its potential by quantifying populations of natural EVs commonly present in human saliva. The method effectively bypasses the difficulty of targeted detection in non-Newtonian fluids and could be used for various applications, from the detection of EVs and viruses in bodily fluids to the detection of molecular clusters or nanoparticles in other complex fluids.
Collapse
Affiliation(s)
| | | | - Aaron Elbourne
- School
of Science, STEM College, RMIT University, Melbourne, VIC 3001, Australia
| | | |
Collapse
|
|
21
|
Wu J, Li Y, Nabi G, Huang X, Zhang X, Wang Y, Huang L. Exosome and lipid metabolism-related genes in pancreatic adenocarcinoma: a prognosis analysis. Aging (Albany NY) 2023; 15:11331-11368. [PMID: 37857015 PMCID: PMC10637811 DOI: 10.18632/aging.205130] [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: 08/01/2023] [Accepted: 09/27/2023] [Indexed: 10/21/2023]
Abstract
OBJECTIVE The purpose of the study was to investigate the role of exosome and lipid metabolism-related genes (EALMRGs) mRNA levels in the diagnosis and prognosis of Pancreatic Adenocarcinoma (PAAD). METHODS The mRNA expression pattern of PAAD and pan-cancers with prognostic data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. EALMRGs were acquired from GeneCards and MSigDB database after merging and deduplication. Prognostic EALMRGs were screened through univariate COX regression analysis, and a prognostic model was constructed based on these genes by least absolute shrinkage and selection operator (LASSO) regression. The prognostic value of EALMRGs was then validated in pan-cancer data. The time characteristics ROC curve analysis was performed to evaluate the effectiveness of the prognostic genes. RESULTS We identified 5 hub genes (ABCB1, CAP1, EGFR, PPARG, SNCA) according to high and low-risk groups of prognoses. The risk formula was verified in three other cohort of pancreatic cancer patients and was explored in pan-cancer data. Additionally, T cell and dendritic cell infiltration was significantly increased in low-risk group. The expression of the 5 hub genes was also identified in single-cell sequencing data of pancreatic cancer with pivotal pathways. Additionally, functional enrichment analysis based on pancreatic cancer data in pancreatic cancer showed that protein serine/threonine kinase activity, focal adhesion, actin binding, cell-substrate junction, organic acid transport, and regulation of transporter activity were significant related to the expression of genes in EALMRGs. CONCLUSIONS Our risk formula shows potential prognostic value in multiple cancers and manifest pivotal alterations in immune infiltration and biological pathway in pancreatic cancer.
Collapse
Affiliation(s)
- Jia Wu
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Yajun Li
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Ghulam Nabi
- Institute of Nature Conservation, Polish Academy of Sciences, Krakow, Poland
| | - Xin Huang
- Department of Gastroenterology, Traditional Chinese Medicine Hospital of Yinchuan, Yinchuan, Ningxia, China
| | - Xu Zhang
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Yuanzhen Wang
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Liya Huang
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| |
Collapse
|
|
22
|
Ungkulpasvich U, Hatakeyama H, Hirotsu T, di Luccio E. Pancreatic Cancer and Detection Methods. Biomedicines 2023; 11:2557. [PMID: 37760999 PMCID: PMC10526344 DOI: 10.3390/biomedicines11092557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/05/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
The pancreas is a vital organ with exocrine and endocrine functions. Pancreatitis is an inflammation of the pancreas caused by alcohol consumption and gallstones. This condition can heighten the risk of pancreatic cancer (PC), a challenging disease with a high mortality rate. Genetic and epigenetic factors contribute significantly to PC development, along with other risk factors. Early detection is crucial for improving PC outcomes. Diagnostic methods, including imagining modalities and tissue biopsy, aid in the detection and analysis of PC. In contrast, liquid biopsy (LB) shows promise in early tumor detection by assessing biomarkers in bodily fluids. Understanding the function of the pancreas, associated diseases, risk factors, and available diagnostic methods is essential for effective management and early PC detection. The current clinical examination of PC is challenging due to its asymptomatic early stages and limitations of highly precise diagnostics. Screening is recommended for high-risk populations and individuals with potential benign tumors. Among various PC screening methods, the N-NOSE plus pancreas test stands out with its high AUC of 0.865. Compared to other commercial products, the N-NOSE plus pancreas test offers a cost-effective solution for early detection. However, additional diagnostic tests are required for confirmation. Further research, validation, and the development of non-invasive screening methods and standardized scoring systems are crucial to enhance PC detection and improve patient outcomes. This review outlines the context of pancreatic cancer and the challenges for early detection.
Collapse
Affiliation(s)
| | | | | | - Eric di Luccio
- Hirotsu Bioscience Inc., 22F The New Otani Garden Court, 4-1 Kioi-cho, Chiyoda-ku, Tokyo 102-0094, Japan; (U.U.); (H.H.); (T.H.)
| |
Collapse
|
|
23
|
Fang Q, Wei Y, Zhang Y, Cao W, Yan L, Kong M, Zhu Y, Xu Y, Guo L, Zhang L, Wang W, Yu Y, Sun J, Yang J. Stem cells as potential therapeutics for hearing loss. Front Neurosci 2023; 17:1259889. [PMID: 37746148 PMCID: PMC10512725 DOI: 10.3389/fnins.2023.1259889] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 08/23/2023] [Indexed: 09/26/2023] Open
Abstract
Hearing impairment is a global health problem. Stem cell therapy has become a cutting-edge approach to tissue regeneration. In this review, the recent advances in stem cell therapy for hearing loss have been discussed. Nanomaterials can modulate the stem cell microenvironment to augment the therapeutic effects further. The potential of combining nanomaterials with stem cells for repairing and regenerating damaged inner ear hair cells (HCs) and spiral ganglion neurons (SGNs) has also been discussed. Stem cell-derived exosomes can contribute to the repair and regeneration of damaged tissue, and the research progress on exosome-based hearing loss treatment has been summarized as well. Despite stem cell therapy's technical and practical limitations, the findings reported so far are promising and warrant further investigation for eventual clinical translation.
Collapse
Affiliation(s)
- Qiaojun Fang
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- School of Life Sciences and Technology, Southeast University, Nanjing, China
| | - Yongjie Wei
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yuhua Zhang
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Wei Cao
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Lin Yan
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Mengdie Kong
- School of Life Sciences and Technology, Southeast University, Nanjing, China
| | - Yongjun Zhu
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yan Xu
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Lingna Guo
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Lei Zhang
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Weiqing Wang
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yafeng Yu
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Jingwu Sun
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Jianming Yang
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| |
Collapse
|
|
24
|
Liang H, Zhang L, Rong J. Potential roles of exosomes in the initiation and metastatic progression of lung cancer. Biomed Pharmacother 2023; 165:115222. [PMID: 37549459 DOI: 10.1016/j.biopha.2023.115222] [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: 05/09/2023] [Revised: 07/17/2023] [Accepted: 07/23/2023] [Indexed: 08/09/2023] Open
Abstract
Lung cancer (LC) incidence and mortality continue to increase annually worldwide. LC is insidious and readily metastasizes and relapses. Except for its early diagnosis and surgical resection, there is no effective cure for advanced metastatic LC, and the prognosis remains dismal. Exosomes, a class of nano-sized extracellular vesicles produced by healthy or diseased cells, are coated with a bilayer lipid membrane and contain various functional molecules such as proteins, lipids, and nucleic acids. They can be used for intracellular or intercellular signaling or the transportation of biological substances. A growing body of evidence supports that exosomes play multiple crucial roles in the occurrence and metastatic progression of many malignancies, including LC. The elucidation of the potential roles of exosomes in the initiation, invasion, and metastasis of LC and their underlying molecular mechanisms may contribute to improved early diagnosis and treatment.
Collapse
Affiliation(s)
- Hongyuan Liang
- Department of Radiology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Shenyang 110004, PR China
| | - Lingyun Zhang
- Department of Medical Oncology, the First Hospital of China Medical University, No. 210 Baita Street, Hunnan District, Shenyang 110001, PR China.
| | - Jian Rong
- Department of Pediatrics, PICU, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Shenyang 110004, PR China.
| |
Collapse
|
|
25
|
Sarkar R, Xu Z, Perera CJ, Apte MV. Emerging role of pancreatic stellate cell-derived extracellular vesicles in pancreatic cancer. Semin Cancer Biol 2023; 93:114-122. [PMID: 37225047 DOI: 10.1016/j.semcancer.2023.05.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 04/17/2023] [Accepted: 05/19/2023] [Indexed: 05/26/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer that is characterised by a prominent collagenous stromal reaction/desmoplasia surrounding tumour cells. Pancreatic stellate cells (PSCs) are responsible for the production of this stroma and have been shown to facilitate PDAC progression. Recently, extracellular vesicles (EVs), in particular, small extracellular vesicles (exosomes) have been a topic of interest in the field of cancer research for their emerging roles in cancer progression and diagnosis. EVs act as a form of intercellular communication by carrying their molecular cargo from one cell to another, regulating functions of the recipient cells. Although the knowledge of the bi-directional interactions between the PSCs and cancer cells that promote disease progression has advanced significantly over the past decade, studies on PSC-derived EVs in PDAC are currently rather limited. This review provides an overview of PDAC, pancreatic stellate cells and their interactions with cancer cells, as well as the currently known role of extracellular vesicles derived from PSCs in PDAC progression.
Collapse
Affiliation(s)
- Rohit Sarkar
- Pancreatic Research Group, South West Sydney Clinical Campuses, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; Ingham Institute of Applied Medical Research, Sydney 2170, Australia
| | - Zhihong Xu
- Pancreatic Research Group, South West Sydney Clinical Campuses, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; Ingham Institute of Applied Medical Research, Sydney 2170, Australia
| | - Chamini J Perera
- Pancreatic Research Group, South West Sydney Clinical Campuses, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; Ingham Institute of Applied Medical Research, Sydney 2170, Australia.
| | - Minoti V Apte
- Pancreatic Research Group, South West Sydney Clinical Campuses, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; Ingham Institute of Applied Medical Research, Sydney 2170, Australia
| |
Collapse
|
|
26
|
Deiana M, Andrés Castán J, Josse P, Kahsay A, Sánchez D, Morice K, Gillet N, Ravindranath R, Patel A, Sengupta P, Obi I, Rodriguez-Marquez E, Khrouz L, Dumont E, Abad Galán L, Allain M, Walker B, Ahn HS, Maury O, Blanchard P, Le Bahers T, Öhlund D, von Hofsten J, Monnereau C, Cabanetos C, Sabouri N. A new G-quadruplex-specific photosensitizer inducing genome instability in cancer cells by triggering oxidative DNA damage and impeding replication fork progression. Nucleic Acids Res 2023; 51:6264-6285. [PMID: 37191066 PMCID: PMC10325911 DOI: 10.1093/nar/gkad365] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 03/31/2023] [Accepted: 04/26/2023] [Indexed: 05/17/2023] Open
Abstract
Photodynamic therapy (PDT) ideally relies on the administration, selective accumulation and photoactivation of a photosensitizer (PS) into diseased tissues. In this context, we report a new heavy-atom-free fluorescent G-quadruplex (G4) DNA-binding PS, named DBI. We reveal by fluorescence microscopy that DBI preferentially localizes in intraluminal vesicles (ILVs), precursors of exosomes, which are key components of cancer cell proliferation. Moreover, purified exosomal DNA was recognized by a G4-specific antibody, thus highlighting the presence of such G4-forming sequences in the vesicles. Despite the absence of fluorescence signal from DBI in nuclei, light-irradiated DBI-treated cells generated reactive oxygen species (ROS), triggering a 3-fold increase of nuclear G4 foci, slowing fork progression and elevated levels of both DNA base damage, 8-oxoguanine, and double-stranded DNA breaks. Consequently, DBI was found to exert significant phototoxic effects (at nanomolar scale) toward cancer cell lines and tumor organoids. Furthermore, in vivo testing reveals that photoactivation of DBI induces not only G4 formation and DNA damage but also apoptosis in zebrafish, specifically in the area where DBI had accumulated. Collectively, this approach shows significant promise for image-guided PDT.
Collapse
Affiliation(s)
- Marco Deiana
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87, Umeå, Sweden
| | | | - Pierre Josse
- Univ Angers, CNRS, MOLTECH-ANJOU, SFR MATRIX, F-49000 Angers, France
| | - Abraha Kahsay
- Department of Integrative Medical Biology, Umeå University, SE-901 87, Umeå, Sweden
| | | | - Korentin Morice
- Univ Angers, CNRS, MOLTECH-ANJOU, SFR MATRIX, F-49000 Angers, France
| | - Natacha Gillet
- ENS de Lyon, CNRS, Université Claude Bernard Lyon 1, Laboratoire de Chimie UMR 5182, F-69342 Lyon, France
| | - Ranjitha Ravindranath
- ENS de Lyon, CNRS, Université Claude Bernard Lyon 1, Laboratoire de Chimie UMR 5182, F-69342 Lyon, France
- Indian Institute for Science Education and Research (IISER), Tirupati-517507, India
| | - Ankit Kumar Patel
- Department of Radiation Sciences/Oncology, Umeå University, SE-901 87, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, SE-901 87, Umeå, Sweden
| | - Pallabi Sengupta
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87, Umeå, Sweden
| | - Ikenna Obi
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87, Umeå, Sweden
| | | | - Lhoussain Khrouz
- ENS de Lyon, CNRS, Université Claude Bernard Lyon 1, Laboratoire de Chimie UMR 5182, F-69342 Lyon, France
| | - Elise Dumont
- ENS de Lyon, CNRS, Université Claude Bernard Lyon 1, Laboratoire de Chimie UMR 5182, F-69342 Lyon, France
- Institut Universitaire de France, 5 rue Descartes, 75005 Paris, France
| | - Laura Abad Galán
- ENS de Lyon, CNRS, Université Claude Bernard Lyon 1, Laboratoire de Chimie UMR 5182, F-69342 Lyon, France
| | - Magali Allain
- Univ Angers, CNRS, MOLTECH-ANJOU, SFR MATRIX, F-49000 Angers, France
| | - Bright Walker
- Department of Chemistry, Kyung Hee University, Seoul, 02447, South Korea
| | - Hyun Seo Ahn
- Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, South Korea
| | - Olivier Maury
- ENS de Lyon, CNRS, Université Claude Bernard Lyon 1, Laboratoire de Chimie UMR 5182, F-69342 Lyon, France
| | | | - Tangui Le Bahers
- ENS de Lyon, CNRS, Université Claude Bernard Lyon 1, Laboratoire de Chimie UMR 5182, F-69342 Lyon, France
- Institut Universitaire de France, 5 rue Descartes, 75005 Paris, France
| | - Daniel Öhlund
- Department of Radiation Sciences/Oncology, Umeå University, SE-901 87, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, SE-901 87, Umeå, Sweden
| | - Jonas von Hofsten
- Department of Integrative Medical Biology, Umeå University, SE-901 87, Umeå, Sweden
| | - Cyrille Monnereau
- ENS de Lyon, CNRS, Université Claude Bernard Lyon 1, Laboratoire de Chimie UMR 5182, F-69342 Lyon, France
| | - Clément Cabanetos
- Univ Angers, CNRS, MOLTECH-ANJOU, SFR MATRIX, F-49000 Angers, France
- Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, South Korea
- Building Blocks for FUture Electronics Laboratory (2BFUEL), IRL CNRS 2002, Yonsei University, Seoul, South Korea
| | - Nasim Sabouri
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87, Umeå, Sweden
| |
Collapse
|
|
27
|
Anoop TM, Basu PK, Chandramohan K, Thomas A, Manoj S. Evolving utility of exosomes in pancreatic cancer management. World J Methodol 2023; 13:46-58. [PMID: 37456979 PMCID: PMC10348087 DOI: 10.5662/wjm.v13.i3.46] [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: 03/22/2023] [Revised: 05/02/2023] [Accepted: 05/31/2023] [Indexed: 06/20/2023] Open
Abstract
Despite the development of newer oncological treatment, the survival of patients with pancreatic cancer (PC) remains poor. Recent studies have identified exosomes as essential mediators of intercellular communications and play a vital role in tumor initiation, metastasis and chemoresistance. Thus, the utility of liquid biopsies using exosomes in PC management can be used for early detection, diagnosis, monitoring as well as drug delivery vehicles for cancer therapy. This review summarizes the function, and clinical applications of exosomes in cancers as minimally invasive liquid biomarker in diagnostic, prognostic and therapeutic roles.
Collapse
Affiliation(s)
- Thattungal Manoharan Anoop
- Department of Medical Oncology, Regional Cancer Center, Medical College Campus, Thiruvananthapuram 695011, Kerala, India
| | - Palash Kumar Basu
- Department of Avionics, Indian Institute of Space Science & Technology (IIST), Thiruvananthapuram 695547, Kerala, India
| | - K Chandramohan
- Surgical Oncology, Regional Cancer Center, Thiruvananthapuram 695011, Kerala, India
| | - Ajai Thomas
- Department of Medical Oncology, Regional Cancer Center, Medical College Campus, Thiruvananthapuram 695011, Kerala, India
| | - S Manoj
- Department of Medical Oncology, Regional Cancer Center, Medical College Campus, Thiruvananthapuram 695011, Kerala, India
| |
Collapse
|
|
28
|
Peng M, Ying Y, Zhang Z, Liu L, Wang W. Reshaping the Pancreatic Cancer Microenvironment at Different Stages with Chemotherapy. Cancers (Basel) 2023; 15:2448. [PMID: 37173915 PMCID: PMC10177210 DOI: 10.3390/cancers15092448] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/09/2023] [Accepted: 04/23/2023] [Indexed: 05/15/2023] Open
Abstract
The dynamic tumor microenvironment, especially the immune microenvironment, during the natural progression and/or chemotherapy treatment is a critical frontier in understanding the effects of chemotherapy on pancreatic cancer. Non-stratified pancreatic cancer patients always receive chemotherapeutic strategies, including neoadjuvant chemotherapy and adjuvant chemotherapy, predominantly according to their physical conditions and different disease stages. An increasing number of studies demonstrate that the pancreatic cancer tumor microenvironment could be reshaped by chemotherapy, an outcome caused by immunogenic cell death, selection and/or education of preponderant tumor clones, adaptive gene mutations, and induction of cytokines/chemokines. These outcomes could in turn impact the efficacy of chemotherapy, making it range from synergetic to resistant and even tumor-promoting. Under chemotherapeutic impact, the metastatic micro-structures in the primary tumor may be built to leak tumor cells into the lymph or blood vasculature, and micro-metastatic/recurrent niches rich in immunosuppressive cells may be recruited by cytokines and chemokines, which provide housing conditions for these circling tumor cells. An in-depth understanding of how chemotherapy reshapes the tumor microenvironment may lead to new therapeutic strategies to block its adverse tumor-promoting effects and prolong survival. In this review, reshaped pancreatic cancer tumor microenvironments due to chemotherapy were reflected mainly in immune cells, pancreatic cancer cells, and cancer-associated fibroblast cells, quantitatively, functionally, and spatially. Additionally, small molecule kinases and immune checkpoints participating in this remodeling process caused by chemotherapy are suggested to be blocked reasonably to synergize with chemotherapy.
Collapse
Affiliation(s)
- Maozhen Peng
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; (M.P.); (Y.Y.); (Z.Z.)
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Ying Ying
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; (M.P.); (Y.Y.); (Z.Z.)
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zheng Zhang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; (M.P.); (Y.Y.); (Z.Z.)
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Liang Liu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; (M.P.); (Y.Y.); (Z.Z.)
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Wenquan Wang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; (M.P.); (Y.Y.); (Z.Z.)
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| |
Collapse
|
|
29
|
Ruze R, Song J, Yin X, Chen Y, Xu R, Wang C, Zhao Y. Mechanisms of obesity- and diabetes mellitus-related pancreatic carcinogenesis: a comprehensive and systematic review. Signal Transduct Target Ther 2023; 8:139. [PMID: 36964133 PMCID: PMC10039087 DOI: 10.1038/s41392-023-01376-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 01/31/2023] [Accepted: 02/15/2023] [Indexed: 03/26/2023] Open
Abstract
Research on obesity- and diabetes mellitus (DM)-related carcinogenesis has expanded exponentially since these two diseases were recognized as important risk factors for cancers. The growing interest in this area is prominently actuated by the increasing obesity and DM prevalence, which is partially responsible for the slight but constant increase in pancreatic cancer (PC) occurrence. PC is a highly lethal malignancy characterized by its insidious symptoms, delayed diagnosis, and devastating prognosis. The intricate process of obesity and DM promoting pancreatic carcinogenesis involves their local impact on the pancreas and concurrent whole-body systemic changes that are suitable for cancer initiation. The main mechanisms involved in this process include the excessive accumulation of various nutrients and metabolites promoting carcinogenesis directly while also aggravating mutagenic and carcinogenic metabolic disorders by affecting multiple pathways. Detrimental alterations in gastrointestinal and sex hormone levels and microbiome dysfunction further compromise immunometabolic regulation and contribute to the establishment of an immunosuppressive tumor microenvironment (TME) for carcinogenesis, which can be exacerbated by several crucial pathophysiological processes and TME components, such as autophagy, endoplasmic reticulum stress, oxidative stress, epithelial-mesenchymal transition, and exosome secretion. This review provides a comprehensive and critical analysis of the immunometabolic mechanisms of obesity- and DM-related pancreatic carcinogenesis and dissects how metabolic disorders impair anticancer immunity and influence pathophysiological processes to favor cancer initiation.
Collapse
Affiliation(s)
- Rexiati Ruze
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Jianlu Song
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Xinpeng Yin
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Yuan Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Ruiyuan Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Chengcheng Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China.
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China.
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China.
| |
Collapse
|
|
30
|
The Roles of Exosomes in Metastasis of Sarcoma: From Biomarkers to Therapeutic Targets. Biomolecules 2023; 13:biom13030456. [PMID: 36979391 PMCID: PMC10046038 DOI: 10.3390/biom13030456] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/21/2023] [Accepted: 02/23/2023] [Indexed: 03/06/2023] Open
Abstract
Sarcoma is a heterogeneous group of mesenchymal neoplasms with a high rate of lung metastasis. The cellular mechanisms responsible for sarcoma metastasis remain poorly understood. Furthermore, there are limited efficacious therapeutic strategies for treating metastatic sarcoma. Improved diagnostic and therapeutic modalities are of increasing importance for the treatment of sarcoma due to their high mortality in the advanced stages of the disease. Recent evidence demonstrates that the exosome, a type of extracellular vesicle released by virtually all cells in the body, is an important facilitator of intercellular communication between the cells and the surrounding environment. The exosome is gaining significant attention among the medical research community, but there is little knowledge about how the exosome affects sarcoma metastasis. In this review, we summarize the multifaceted roles of sarcoma-derived exosomes in promoting the process of metastasis via the formation of pre-metastatic niche (PMN), the regulation of immunity, angiogenesis, vascular permeability, and the migration of sarcoma cells. We also highlight the potential of exosomes as innovative diagnostic and prognostic biomarkers as well as therapeutic targets in sarcoma metastasis.
Collapse
|
|
31
|
Dwivedi M, Ghosh D, Saha A, Hasan S, Jindal D, Yadav H, Yadava A, Dwivedi M. Biochemistry of exosomes and their theranostic potential in human diseases. Life Sci 2023; 315:121369. [PMID: 36639052 DOI: 10.1016/j.lfs.2023.121369] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 12/22/2022] [Accepted: 01/01/2023] [Indexed: 01/11/2023]
Abstract
Exosomes are classified as special extracellular vesicles in the eukaryotic system having diameters ranging from 30 to 120 nm. These vesicles carry various endogenous molecules including DNA, mRNA, microRNA, circular RNA, and proteins, crucial for numerous metabolic reactions and can be proposed as therapeutic or diagnostic targets for several disorders. The donor exosomes release their content to recipient cells and further establish the significant intercellular communication showing biological effects by triggering environmental alterations. Exosomes derived from mesenchymal and dendritic cells have demonstrated their therapeutic potential against organ injury. Yet, various intricacies are involved in exosomal transport and its inclusion in cancer and other disease pathogenesis needs to be explored. The exosomes represent profound potential as diagnostic biomarkers and therapeutic carriers in various pathophysiological conditions such as neurodegenerative diseases, chronic cancers, infectious diseases, female reproductive diseases and cardiovascular diseases. In the current study, we demonstrate the advancements in the implication of exosomes as one of the irrefutable prognostic biological targets in human health and diseases.
Collapse
Affiliation(s)
- Manish Dwivedi
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, India.
| | - Diya Ghosh
- Department of Biotechnology, Heritage Institute of Technology, Kolkata, West Bengal, India
| | - Anwesha Saha
- Department of Biotechnology, Heritage Institute of Technology, Kolkata, West Bengal, India
| | - Saba Hasan
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, India
| | - Divya Jindal
- Center for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, India
| | - Hitendra Yadav
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, India
| | - Anuradha Yadava
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, India
| | - Medha Dwivedi
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, India
| |
Collapse
|
|
32
|
Gong X, Chi H, Strohmer DF, Teichmann AT, Xia Z, Wang Q. Exosomes: A potential tool for immunotherapy of ovarian cancer. Front Immunol 2023; 13:1089410. [PMID: 36741380 PMCID: PMC9889675 DOI: 10.3389/fimmu.2022.1089410] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 12/30/2022] [Indexed: 01/19/2023] Open
Abstract
Ovarian cancer is a malignant tumor of the female reproductive system, with a very poor prognosis and high mortality rates. Chemotherapy and radiotherapy are the most common treatments for ovarian cancer, with unsatisfactory results. Exosomes are a subpopulation of extracellular vesicles, which have a diameter of approximately 30-100 nm and are secreted by many different types of cells in various body fluids. Exosomes are highly stable and are effective carriers of immunotherapeutic drugs. Recent studies have shown that exosomes are involved in various cellular responses in the tumor microenvironment, influencing the development and therapeutic efficacy of ovarian cancer, and exhibiting dual roles in inhibiting and promoting tumor development. Exosomes also contain a variety of genes related to ovarian cancer immunotherapy that could be potential biomarkers for ovarian cancer diagnosis and prognosis. Undoubtedly, exosomes have great therapeutic potential in the field of ovarian cancer immunotherapy. However, translation of this idea to the clinic has not occurred. Therefore, it is important to understand how exosomes could be used in ovarian cancer immunotherapy to regulate tumor progression. In this review, we summarize the biomarkers of exosomes in different body fluids related to immunotherapy in ovarian cancer and the potential mechanisms by which exosomes influence immunotherapeutic response. We also discuss the prospects for clinical application of exosome-based immunotherapy in ovarian cancer.
Collapse
Affiliation(s)
| | - Hao Chi
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Dorothee Franziska Strohmer
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Alexander Tobias Teichmann
- Sichuan Provincial Center for Gynecology and Breast Diseases (Gynecology), Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Zhijia Xia
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Qin Wang
- Sichuan Provincial Center for Gynecology and Breast Diseases (Gynecology), Affiliated Hospital of Southwest Medical University, Luzhou, China
| |
Collapse
|
|
33
|
Modified lipidomic profile of cancer-associated small extracellular vesicles facilitates tumorigenic behaviours and contributes to disease progression. Adv Biol Regul 2023; 87:100935. [PMID: 36443198 DOI: 10.1016/j.jbior.2022.100935] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/10/2022] [Accepted: 11/15/2022] [Indexed: 11/23/2022]
Abstract
Metabolic rewiring is a key feature of cancer cells, which involves the alteration of amino acids, glucose and lipids to support aggressive cancer phenotypes. Changes in lipid metabolism alter cancer growth characteristics, membrane integrity and signalling pathways. Small extracellular vesicles (sEVs) are membrane-bound vesicles secreted by cells into the extracellular environment, where they participate in cell-to-cell communication. Lipids are involved in the formation and cargo assortment of sEVs, resulting in their selective packaging in these vesicles. Further, sEVs participate in different aspects of cancer development, such as proliferation, migration and angiogenesis. Various lipidomic studies have indicated the enrichment of specific lipids in sEVs derived from tumour cells, which aid in their pathological functioning. This paper summarises how the modified lipid profile of sEVs contributes to carcinogenesis and disease progression.
Collapse
|
|
34
|
A soluble pH-responsive host-guest-based nanosystem for homogeneous exosomes capture with high-efficiency. CHINESE CHEM LETT 2023. [DOI: 10.1016/j.cclet.2023.108129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
|
|
35
|
Wang M, Qin Z, Wan J, Yan Y, Duan X, Yao X, Jiang Z, Li W, Qin Z. Tumor-derived exosomes drive pre-metastatic niche formation in lung via modulating CCL1+ fibroblast and CCR8+ Treg cell interactions. Cancer Immunol Immunother 2022; 71:2717-2730. [DOI: 10.1007/s00262-022-03196-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 03/25/2022] [Indexed: 10/18/2022]
|
|
36
|
Molecular Docking and Intracellular Translocation of Extracellular Vesicles for Efficient Drug Delivery. Int J Mol Sci 2022; 23:ijms232112971. [PMID: 36361760 PMCID: PMC9659046 DOI: 10.3390/ijms232112971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 10/07/2022] [Accepted: 10/21/2022] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs), including exosomes, mediate intercellular communication by delivering their contents, such as nucleic acids, proteins, and lipids, to distant target cells. EVs play a role in the progression of several diseases. In particular, programmed death-ligand 1 (PD-L1) levels in exosomes are associated with cancer progression. Furthermore, exosomes are being used for new drug-delivery systems by modifying their membrane peptides to promote their intracellular transduction via micropinocytosis. In this review, we aim to show that an efficient drug-delivery system and a useful therapeutic strategy can be established by controlling the molecular docking and intracellular translocation of exosomes. We summarise the mechanisms of molecular docking of exosomes, the biological effects of exosomes transmitted into target cells, and the current state of exosomes as drug delivery systems.
Collapse
|
|
37
|
Jiang W, Li X, Xiang C, Zhou W. Neutrophils in pancreatic cancer: Potential therapeutic targets. Front Oncol 2022; 12:1025805. [PMID: 36324574 PMCID: PMC9618950 DOI: 10.3389/fonc.2022.1025805] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 09/28/2022] [Indexed: 08/30/2023] Open
Abstract
Pancreatic cancer is a digestive system malignancy and poses a high mortality worldwide. Traditionally, neutrophils have been thought to play a role in acute inflammation. In contrast, their importance during tumor diseases has been less well studied. Generally, neutrophils are recruited into the tumor microenvironment and exert inflammation and tumor-promoting effects. As an essential part of the tumor microenvironment, neutrophils play diverse roles in pancreatic cancer, such as angiogenesis, progression, metastasis and immunosuppression. Additionally, neutrophils can be a new potential therapeutic target in cancer. Inhibitors of cytokines, chemokines and neutrophil extracellular traps can exert antitumor effects. In this review, we describe the role of neutrophils in the development and progression of pancreatic cancer, discuss their potential as therapeutic targets, and aim to provide ideas for improving the prognosis of patients with this malignant tumor disease.
Collapse
Affiliation(s)
- Wenkai Jiang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Xin Li
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Caifei Xiang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Wence Zhou
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
| |
Collapse
|
|
38
|
Huang X, Zhang G, Tang TY, Gao X, Liang TB. Personalized pancreatic cancer therapy: from the perspective of mRNA vaccine. Mil Med Res 2022; 9:53. [PMID: 36224645 PMCID: PMC9556149 DOI: 10.1186/s40779-022-00416-w] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 09/14/2022] [Indexed: 11/25/2022] Open
Abstract
Pancreatic cancer is characterized by inter-tumoral and intra-tumoral heterogeneity, especially in genetic alteration and microenvironment. Conventional therapeutic strategies for pancreatic cancer usually suffer resistance, highlighting the necessity for personalized precise treatment. Cancer vaccines have become promising alternatives for pancreatic cancer treatment because of their multifaceted advantages including multiple targeting, minimal nonspecific effects, broad therapeutic window, low toxicity, and induction of persistent immunological memory. Multiple conventional vaccines based on the cells, microorganisms, exosomes, proteins, peptides, or DNA against pancreatic cancer have been developed; however, their overall efficacy remains unsatisfactory. Compared with these vaccine modalities, messager RNA (mRNA)-based vaccines offer technical and conceptional advances in personalized precise treatment, and thus represent a potentially cutting-edge option in novel therapeutic approaches for pancreatic cancer. This review summarizes the current progress on pancreatic cancer vaccines, highlights the superiority of mRNA vaccines over other conventional vaccines, and proposes the viable tactic for designing and applying personalized mRNA vaccines for the precise treatment of pancreatic cancer.
Collapse
Affiliation(s)
- Xing Huang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
| | - Gang Zhang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
| | - Tian-Yu Tang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
| | - Xiang Gao
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
| | - Ting-Bo Liang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
| |
Collapse
|
|
39
|
Druk IV. Pancreatic cancer, pancreatogenic diabetes, type 2 diabetes mellitus. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2022:171-182. [DOI: 10.31146/1682-8658-ecg-205-9-171-182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Pancreatic cancer (PC) is the fourth leading cause of death among all types of cancer. PC is very aggressive with a low 5-year overall survival rate. The highest prevalence of diabetes mellitus (DM), significantly exceeding the average population, is registered among patients with prostate cancer Recommendations for systemic screening of patients with diabetes for the detection of PC are not standardized. The purpose of this review is to present an analysis of current literature data on pathogenetic relationships between DM and PC and prospects for PC screening. Research data indicate that there is a bidirectional relationship between DM and PC, in which DM can act either as a risk factor for PC or as a marker of paraneoplastic syndrome of PC. In the differential diagnosis of type 2 diabetes, pancreatogenic diabetes and diabetes associated with PC, a set of clinical signs can be used. Patients with DM who have additional signs/symptoms of increased risk can be considered as a group subject to mandatory screening. Numerous studies of various proteomic, metabolomic, genetic and transcriptomic biomarkers PC have been published. The search for an easy-to-use clinically useful and cost-effective PC marker is still ongoing.
Collapse
|
|
40
|
Composition, Biogenesis, and Role of Exosomes in Tumor Development. Stem Cells Int 2022; 2022:8392509. [PMID: 36117723 PMCID: PMC9481374 DOI: 10.1155/2022/8392509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 08/14/2022] [Accepted: 08/26/2022] [Indexed: 11/30/2022] Open
Abstract
The role of exosomes and their mechanism of action at the tumor site have received increasing attention. These microvesicles are produced by a wide range of cells including mesenchymal stem cells (MSCs) and immune cells. In particular, tumor cells release remarkable amounts of exosomes which spread to distant organs through the blood and enhance the possibility of tumor metastasis. In spite of results on tumor promoting properties, there are reports demonstrating the tumor inhibiting effects of exosomes depending on the type of the tumor and cell source. This review aims to have a comprehensive appraisal on the biogenesis, composition, and isolation of exosomes and then highlights the current knowledge of their role in cancer progression or inhibition by special focusing on MSC's exosomes (MSC-EXOs).
Collapse
|
|
41
|
Chen Z, Lu M, Zhang Y, Wang H, Zhou J, Zhou M, Zhang T, Song J. Oxidative stress state inhibits exosome secretion of hPDLCs through a specific mechanism mediated by PRMT1. J Periodontal Res 2022; 57:1101-1115. [PMID: 36063421 DOI: 10.1111/jre.13040] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 06/14/2022] [Accepted: 07/13/2022] [Indexed: 10/14/2022]
Abstract
BACKGROUND AND OBJECTIVES Periodontitis, the most common chronic inflammation characterized by persistent alveolar bone resorption in the periodontitis, affects almost half of the adult population worldwide. Oxidative stress is one of the pathophysiological mechanisms underlying periodontitis, which affects the occurrence and development of periodontitis. Exosomes are increasingly recognized as vehicles of intercellular communication and are closely related to periodontitis. However, the effects of oxidative stress on exosome secretion and the specific mechanisms remain elusive in human periodontal ligament cells (hPDLCs). The relationship between exosome secretion and the osteogenic differentiation of hPDLCs also needs to be investigated. METHODS Isolated PDLSCs were identified using flow cytometry. Osteogenesis was measured using alizarin red staining and ALP staining. Expression of exosomal markers and PRMT1 was analyzed using western blot. Immunofluorescence was used to measure exosome uptake and the expression of EEA1. RESULTS The secretion capacity of exosomes was markedly suppressed under oxidative stress. Protein arginine methyltransferase 1 (PRMT1) has been strongly associated with both oxidative stress and inflammation, and PRMT1 was significantly upregulated under oxidative stress conditions. Lentivirus-mediated overexpression of PRMT1 caused a significant reduction in the secretion of exosomes, but multivesicular bodies (MVBs) containing a large number of intraluminal vesicles (ILVs) were increased. Rab11a and Rab27a expression, which mediate MVBs fusion with cell membranes, decreased, although this phenomenon was restored after knocking down PRMT1 expression under oxidative stress. CONCLUSIONS These results indicated that PRMT1 mediated a decrease in exosome secretion of hPDLCs. The decrease in Rab11a and Rab27a leads to a large accumulation of MVBs in cells and is one of the main reasons for impaired exosome secretion. The decrease in osteogenic differentiation of hPDLCs caused by H2 O2 may originate in part from the inhibition of exosome secretion.
Collapse
Affiliation(s)
- Ziqi Chen
- College of Stomatology, Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China.,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Miao Lu
- College of Stomatology, Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China.,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Yanan Zhang
- College of Stomatology, Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China.,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - He Wang
- College of Stomatology, Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China.,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Jie Zhou
- College of Stomatology, Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China.,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Mengjiao Zhou
- College of Stomatology, Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China.,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Tingwei Zhang
- College of Stomatology, Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China.,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Jinlin Song
- College of Stomatology, Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China.,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| |
Collapse
|
|
42
|
Tang Y, Gao G, Xia WW, Wang JB. METTL3 promotes the growth and metastasis of pancreatic cancer by regulating the m6A modification and stability of E2F5. Cell Signal 2022; 99:110440. [PMID: 35985439 DOI: 10.1016/j.cellsig.2022.110440] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 07/28/2022] [Accepted: 08/12/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Pancreatic cancer belongs to lethal cancer with limited efficient treatment currently, and its main cause of death is rapid tumor growth and early metastasis. N6-methyladenosine (m6A) modification is a new method of epigenetic gene regulation involved in tumor progression, in which methyltransferase-like 3(METTL3) is the sole catalytic subunit. However, the role of METTL3 in pancreatic cancer remains to be explored. METHODS m6A level was measured using MeRIP assay, and RT-qPCR and western blot were applied to determine mRNA and protein expression, respectively. Cellular behaviors were detected using CCK-8, EdU, wound healing and transwell assays. Xenograft assays were conducted to further verify the roles of METTL3 in pancreatic cancer. RESULTS METTL3 was highly expressed in pancreatic cancer. However, downregulation of METTL3 restrained the viability, migration and invasion of pancreatic cancer cells. Moreover, E2F5 was found to be positively regulated by METTL3. Intriguingly, the anti-tumor functions of METTL3 knockdown in the phenotype of pancreatic cancer cells were overturned by overexpression of E2F5. Silencing METTL3 resulted in the decreased stability of E2F5 by methylating E2F5. CONCLUSIONS In conclusion, METTL3 can promote the malignant progression of pancreatic cancer by modifying E2F5 through m6A methylation to promote its stability.
Collapse
Affiliation(s)
- Yan Tang
- Department of Radiology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Guo Gao
- Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Wen-Wen Xia
- Department of Pathology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jing-Bo Wang
- Department of Radiology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
43
|
Abstract
OBJECTIVES Extracellular vesicles (EVs) are lipid bound vesicles secreted by cells into the extracellular environment. Studies have implicated EVs in cell proliferation, epithelial-mesenchymal transition, metastasis, angiogenesis, and mediating the interaction of tumor cells and microenvironment. A systematic characterization of EVs from pancreatic cancer cells and cancer-associated fibroblasts (CAFs) would be valuable for studying the roles of EV proteins in pancreatic tumorigenesis. METHODS Proteomic and functional analyses were applied to characterize the proteomes of EVs released from 5 pancreatic cancer lines, 2 CAF cell lines, and a normal pancreatic epithelial cell line (HPDE). RESULTS More than 1400 nonredundant proteins were identified in each EV derived from the cell lines. The majority of the proteins identified in the EVs from the cancer cells, CAFs, and HPDE were detected in all 3 groups, highly enriched in the biological processes of vesicle-mediated transport and exocytosis. Protein networks relevant to pancreatic tumorigenesis, including epithelial-mesenchymal transition, complement, and coagulation components, were significantly enriched in the EVs from cancer cells or CAFs. CONCLUSIONS These findings support the roles of EVs as a potential mediator in transmitting epithelial-mesenchymal transition signals and complement response in the tumor microenvironment and possibly contributing to coagulation defects related to cancer development.
Collapse
|
|
44
|
Mirzaei S, Paskeh MDA, Okina E, Gholami MH, Hushmandi K, Hashemi M, Kalu A, Zarrabi A, Nabavi N, Rabiee N, Sharifi E, Karimi-Maleh H, Ashrafizadeh M, Kumar AP, Wang Y. Molecular Landscape of LncRNAs in Prostate Cancer: A focus on pathways and therapeutic targets for intervention. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:214. [PMID: 35773731 PMCID: PMC9248128 DOI: 10.1186/s13046-022-02406-1] [Citation(s) in RCA: 104] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 05/27/2022] [Indexed: 02/08/2023]
Abstract
Background One of the most malignant tumors in men is prostate cancer that is still incurable due to its heterogenous and progressive natures. Genetic and epigenetic changes play significant roles in its development. The RNA molecules with more than 200 nucleotides in length are known as lncRNAs and these epigenetic factors do not encode protein. They regulate gene expression at transcriptional, post-transcriptional and epigenetic levels. LncRNAs play vital biological functions in cells and in pathological events, hence their expression undergoes dysregulation. Aim of review The role of epigenetic alterations in prostate cancer development are emphasized here. Therefore, lncRNAs were chosen for this purpose and their expression level and interaction with other signaling networks in prostate cancer progression were examined. Key scientific concepts of review The aberrant expression of lncRNAs in prostate cancer has been well-documented and progression rate of tumor cells are regulated via affecting STAT3, NF-κB, Wnt, PI3K/Akt and PTEN, among other molecular pathways. Furthermore, lncRNAs regulate radio-resistance and chemo-resistance features of prostate tumor cells. Overexpression of tumor-promoting lncRNAs such as HOXD-AS1 and CCAT1 can result in drug resistance. Besides, lncRNAs can induce immune evasion of prostate cancer via upregulating PD-1. Pharmacological compounds such as quercetin and curcumin have been applied for targeting lncRNAs. Furthermore, siRNA tool can reduce expression of lncRNAs thereby suppressing prostate cancer progression. Prognosis and diagnosis of prostate tumor at clinical course can be evaluated by lncRNAs. The expression level of exosomal lncRNAs such as lncRNA-p21 can be investigated in serum of prostate cancer patients as a reliable biomarker.
Collapse
Affiliation(s)
- Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Mahshid Deldar Abad Paskeh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.,Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elena Okina
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.,NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, 180554, Singapore, Singapore
| | | | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.,Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Azuma Kalu
- School of Life, Health & Chemical Sciences, The Open University, Milton Keynes, United Kingdom.,Pathology, Sheffield Teaching Hospital, Sheffield, United Kingdom
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, 34396, Istanbul, Turkey
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, V6H3Z6, Vancouver, BC, Canada
| | - Navid Rabiee
- Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Nam-gu, Pohang, Gyeongbuk, 37673, Korea.,School of Engineering, Macquarie University, Sydney, New South Wales, 2109, Australia
| | - Esmaeel Sharifi
- Department of Tissue Engineering and Biomaterials, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, 6517838736, Iran
| | - Hassan Karimi-Maleh
- School of Resources and Environment, University of Electronic Science and Technology of China, P.O. Box 611731, Xiyuan Ave, Chengdu, PR China.,Department of Chemical Engineering, Quchan University of Technology, Quchan, Iran.,Department of Chemical Sciences, University of Johannesburg, Doornfontein Campus, Johannesburg, 2028, South Africa
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, 34956, Istanbul, Turkey.
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore. .,NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, 180554, Singapore, Singapore.
| | - Yuzhuo Wang
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, V6H3Z6, Vancouver, BC, Canada.
| |
Collapse
|
|
45
|
Jia Z, Jia J, Yao L, Li Z. Crosstalk of Exosomal Non-Coding RNAs in The Tumor Microenvironment: Novel Frontiers. Front Immunol 2022; 13:900155. [PMID: 35663957 PMCID: PMC9162146 DOI: 10.3389/fimmu.2022.900155] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 04/22/2022] [Indexed: 12/18/2022] Open
Abstract
The tumor microenvironment (TME) is defined as a complex and dynamic tissue entity composed of endothelial, stromal, immune cells, and the blood system. The homeostasis and evolution of the TME are governed by intimate interactions among cellular compartments. The malignant behavior of cancer cells, such as infiltrating growth, proliferation, invasion, and metastasis, is predominantly dependent on the bidirectional communication between tumor cells and the TME. And such dialogue mainly involves the transfer of multifunctional regulatory molecules from tumor cells and/or stromal cells within the TME. Interestingly, increasing evidence has confirmed that exosomes carrying regulatory molecules, proteins, and nucleic acids act as an active link in cellular crosstalk in the TME. Notably, extensive studies have identified non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), that could be encapsulated by exosomes, which regulate the coordinated function within the TME and thus participate in cancer development and progression. In this review, we summarize recent literature around the topic of the functions and mechanisms of exosomal ncRNAs in the TME and highlight their clinical significance.
Collapse
Affiliation(s)
- Zimo Jia
- Department of Biochemistry and Molecular Biology, Hebei Medical University, Shijiazhuang, China.,The Second General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jinlin Jia
- National Research Institute for Family Planning, National Human Genetic Resources Center, Beijing, China.,Graduate School, Peking Union Medical College, Beijing, China
| | - Lihui Yao
- Department of Otolaryngology, Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
| | - Zhihan Li
- The Second General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| |
Collapse
|
|
46
|
Bunduc S, Gede N, Váncsa S, Lillik V, Kiss S, Juhász MF, Erőss B, Szakács Z, Gheorghe C, Mikó A, Hegyi P. Exosomes as prognostic biomarkers in pancreatic ductal adenocarcinoma-a systematic review and meta-analysis. Transl Res 2022; 244:126-136. [PMID: 35066189 DOI: 10.1016/j.trsl.2022.01.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 01/09/2022] [Accepted: 01/13/2022] [Indexed: 01/06/2023]
Abstract
Extensive research is focused on the role of liquid biopsy in pancreatic cancer since reliable diagnostic and follow-up biomarkers represent an unmet need for this highly lethal malignancy. We performed a systematic review and meta-analysis on the prognostic value of exosomal biomarkers in pancreatic ductal adenocarcinoma (PDAC). MEDLINE, Embase, Scopus, Web of Science, and CENTRAL were systematically searched on the 18th of January, 2021 for studies reporting on the differences in overall (OS) and progression-free survival (PFS) in PDAC patients with positive vs negative exosomal biomarkers isolated from blood. The random-effects model estimated pooled multivariate-adjusted (AHR) and univariate hazard ratios (UHRs) with 95% confidence intervals (CIs). Eleven studies comprising 634 patients were eligible for meta-analysis. Detection of positive exosomal biomarkers indicated increased risk of mortality (UHR = 2.81, CI:1.31-6,00, I2 = 88.7%, P < 0.001), and progression (UHR = 3.33, CI: 2.33-4.77, I2 = 0, P = 0.879) across various disease stages. Positive exosomal biomarkers identified preoperatively revealed a higher risk of mortality in resectable stages (UHR = 5.55, CI: 3.24-9.49, I2 = 0, P = 0.898). The risk of mortality in unresectable stages was not significantly increased with positive exosomal biomarkers (UHR = 2.51, CI: 0.55-11.43, I2 = 90.3%, P < 0.001). Detectable exosomal micro ribonucleic acids were associated with a decreased OS (UHR = 4.08, CI: 2.16-7.69, I2 = 46.9%, P = 0.152) across various stages. Our results reflect the potential of exosomal biomarkers for prognosis evaluation in PDAC. The associated heterogeneity reflects the variability of study methods and need for their uniformization before transition to clinical use.
Collapse
Affiliation(s)
- Stefania Bunduc
- Institute for Translational Medicine, Medical School, University of Pécs, 7624 Pécs, Szigeti ú;t 12, Hungary; Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; Fundeni Clinical Institute, 022328 Bucharest, Romania; Center for Translational Medicine, Semmelweis University, 1085 Budapest, Üllői út 26, Hungary; Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, 1085 Budapest, Baross út 22-24, Hungary
| | - Noémi Gede
- Institute for Translational Medicine, Medical School, University of Pécs, 7624 Pécs, Szigeti ú;t 12, Hungary; János Szentágothai Research Center, University of Pécs, 7624 Pécs, Szigeti út 12, Hungary
| | - Szilárd Váncsa
- Institute for Translational Medicine, Medical School, University of Pécs, 7624 Pécs, Szigeti ú;t 12, Hungary; János Szentágothai Research Center, University of Pécs, 7624 Pécs, Szigeti út 12, Hungary; Center for Translational Medicine, Semmelweis University, 1085 Budapest, Üllői út 26, Hungary; Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, 1085 Budapest, Baross út 22-24, Hungary
| | - Veronika Lillik
- Institute for Translational Medicine, Medical School, University of Pécs, 7624 Pécs, Szigeti ú;t 12, Hungary
| | - Szabolcs Kiss
- Institute for Translational Medicine, Medical School, University of Pécs, 7624 Pécs, Szigeti ú;t 12, Hungary; Doctoral School of Clinical Medicine, University of Szeged, 6720, Hungary
| | - Márk Félix Juhász
- Institute for Translational Medicine, Medical School, University of Pécs, 7624 Pécs, Szigeti ú;t 12, Hungary; János Szentágothai Research Center, University of Pécs, 7624 Pécs, Szigeti út 12, Hungary; Center for Translational Medicine, Semmelweis University, 1085 Budapest, Üllői út 26, Hungary
| | - Bálint Erőss
- Institute for Translational Medicine, Medical School, University of Pécs, 7624 Pécs, Szigeti ú;t 12, Hungary; János Szentágothai Research Center, University of Pécs, 7624 Pécs, Szigeti út 12, Hungary; Center for Translational Medicine, Semmelweis University, 1085 Budapest, Üllői út 26, Hungary; Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, 1085 Budapest, Baross út 22-24, Hungary
| | - Zsolt Szakács
- Institute for Translational Medicine, Medical School, University of Pécs, 7624 Pécs, Szigeti ú;t 12, Hungary; First Department of Medicine, Medical School, University of Pécs, 7624 Pécs, Szigeti út 12 Hungary
| | - Cristian Gheorghe
- Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Alexandra Mikó
- Institute for Translational Medicine, Medical School, University of Pécs, 7624 Pécs, Szigeti ú;t 12, Hungary; Department of Medical Genetics, Medical School, University of Pécs, 7623, Pécs, József Attila út 7
| | - Péter Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, 7624 Pécs, Szigeti ú;t 12, Hungary; János Szentágothai Research Center, University of Pécs, 7624 Pécs, Szigeti út 12, Hungary; Center for Translational Medicine, Semmelweis University, 1085 Budapest, Üllői út 26, Hungary; Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, 1085 Budapest, Baross út 22-24, Hungary.
| |
Collapse
|
|
47
|
Koltai T, Reshkin SJ, Carvalho TMA, Di Molfetta D, Greco MR, Alfarouk KO, Cardone RA. Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma: A Physiopathologic and Pharmacologic Review. Cancers (Basel) 2022; 14:2486. [PMID: 35626089 PMCID: PMC9139729 DOI: 10.3390/cancers14102486] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a poor prognosis and inadequate response to treatment. Many factors contribute to this therapeutic failure: lack of symptoms until the tumor reaches an advanced stage, leading to late diagnosis; early lymphatic and hematic spread; advanced age of patients; important development of a pro-tumoral and hyperfibrotic stroma; high genetic and metabolic heterogeneity; poor vascular supply; a highly acidic matrix; extreme hypoxia; and early development of resistance to the available therapeutic options. In most cases, the disease is silent for a long time, andwhen it does become symptomatic, it is too late for ablative surgery; this is one of the major reasons explaining the short survival associated with the disease. Even when surgery is possible, relapsesare frequent, andthe causes of this devastating picture are the low efficacy ofand early resistance to all known chemotherapeutic treatments. Thus, it is imperative to analyze the roots of this resistance in order to improve the benefits of therapy. PDAC chemoresistance is the final product of different, but to some extent, interconnected factors. Surgery, being the most adequate treatment for pancreatic cancer and the only one that in a few selected cases can achieve longer survival, is only possible in less than 20% of patients. Thus, the treatment burden relies on chemotherapy in mostcases. While the FOLFIRINOX scheme has a slightly longer overall survival, it also produces many more adverse eventsso that gemcitabine is still considered the first choice for treatment, especially in combination with other compounds/agents. This review discusses the multiple causes of gemcitabine resistance in PDAC.
Collapse
Affiliation(s)
| | - Stephan Joel Reshkin
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Tiago M. A. Carvalho
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Daria Di Molfetta
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Khalid Omer Alfarouk
- Zamzam Research Center, Zamzam University College, Khartoum 11123, Sudan;
- Alfarouk Biomedical Research LLC, Temple Terrace, FL 33617, USA
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| |
Collapse
|
|
48
|
Popov A, Mandys V. Senescence-Associated miRNAs and Their Role in Pancreatic Cancer. Pathol Oncol Res 2022; 28:1610156. [PMID: 35570840 PMCID: PMC9098800 DOI: 10.3389/pore.2022.1610156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 04/12/2022] [Indexed: 01/17/2023]
Abstract
Replicative senescence is irreversible cell proliferation arrest for somatic cells which can be circumvented in cancers. Cellular senescence is a process, which may play two opposite roles. On the one hand, this is a natural protection of somatic cells against unlimited proliferation and malignant transformation. On the other hand, cellular secretion caused by senescence can stimulate inflammation and proliferation of adjacent cells that may promote malignancy. The main genes controlling the senescence pathways are also well known as tumor suppressors. Almost 140 genes regulate both cellular senescence and cancer pathways. About two thirds of these genes (64%) are regulated by microRNAs. Senescence-associated miRNAs can stimulate cancer progression or act as tumor suppressors. Here we review the role playing by senescence-associated miRNAs in development, diagnostics and treatment of pancreatic cancer.
Collapse
Affiliation(s)
- Alexey Popov
- Department of Pathology, Third Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, Prague, Czechia
| | | |
Collapse
|
|
49
|
Role of tumour-derived exosomes in metastasis. Biomed Pharmacother 2022; 147:112657. [DOI: 10.1016/j.biopha.2022.112657] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/15/2022] [Accepted: 01/18/2022] [Indexed: 12/15/2022] Open
|
|
50
|
Paskeh MDA, Mehrabi A, Gholami MH, Zabolian A, Ranjbar E, Saleki H, Ranjbar A, Hashemi M, Ertas YN, Hushmandi K, Mirzaei S, Ashrafizadeh M, Zarrabi A, Samarghandian S. EZH2 as a new therapeutic target in brain tumors: Molecular landscape, therapeutic targeting and future prospects. Biomed Pharmacother 2022; 146:112532. [PMID: 34906772 DOI: 10.1016/j.biopha.2021.112532] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 12/02/2021] [Accepted: 12/08/2021] [Indexed: 12/20/2022] Open
Abstract
Brain tumors are responsible for high mortality and morbidity worldwide. The brain tumor treatment depends on identification of molecular pathways involved in progression and malignancy. Enhancer of zeste homolog 2 (EZH2) has obtained much attention in recent years in field of cancer therapy due to its aberrant expression and capacity in modulating expression of genes by binding to their promoter and affecting methylation status. The present review focuses on EZH2 signaling in brain tumors including glioma, glioblastoma, astrocytoma, ependymomas, medulloblastoma and brain rhabdoid tumors. EZH2 signaling mainly participates in increasing proliferation and invasion of cancer cells. However, in medulloblastoma, EZH2 demonstrates tumor-suppressor activity. Furthermore, EZH2 can regulate response of brain tumors to chemotherapy and radiotherapy. Various molecular pathways can function as upstream mediators of EZH2 in brain tumors including lncRNAs and miRNAs. Owing to its enzymatic activity, EZH2 can bind to promoter of target genes to induce methylation and affects their expression. EZH2 can be considered as an independent prognostic factor in brain tumors that its upregulation provides undesirable prognosis. Both anti-tumor agents and gene therapies such as siRNA have been developed for targeting EZH2 in cancer therapy.
Collapse
Affiliation(s)
- Mahshid Deldar Abad Paskeh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Atefeh Mehrabi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Amirhossein Zabolian
- Department of Orthopedics, School of Medicine, 5th Azar Hospital, Golestan University of Medical Sciences, Golestan, Iran
| | - Ehsan Ranjbar
- Yadegar-e-Imam Khomeini (RAH) Shahre Rey Branch, Islamic Azad University, Tehran, Iran
| | - Hossein Saleki
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Adnan Ranjbar
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Yavuz Nuri Ertas
- Department of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey; ERNAM-Nanotechnology Research and Application Center, Erciyes University, Kayseri 38039, Turkey
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran.
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, Istanbul, Turkey; Sabanci University Nanotechnology Research and Application Center (SUNUM), Istanbul, Turkey
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Turkey
| | - Saeed Samarghandian
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran.
| |
Collapse
|