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1
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Hasan R, Zhao Z, Li Y, Liu Y, Zhang Y, Cheng K. Small extracellular vesicles (sEVs) in pancreatic cancer progression and diagnosis. J Control Release 2025; 380:269-282. [PMID: 39889882 PMCID: PMC11908897 DOI: 10.1016/j.jconrel.2025.01.072] [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: 10/16/2024] [Revised: 01/16/2025] [Accepted: 01/24/2025] [Indexed: 02/03/2025]
Abstract
Pancreatic cancer is one of the most aggressive malignancies with poor prognostic outcomes, necessitating the exploration of novel biomarkers and therapeutic targets for early detection and effective treatment. Small extracellular vesicles (sEVs) secreted by cells, have gained considerable attention in cancer research due to their role in intercellular communication and their potential as non-invasive biomarkers. This review focuses on the role of sEVs in the progression of pancreatic cancer and their application as biomarkers. We delve into the biogenesis, composition, and functional implications of sEVs in pancreatic tumor biology, emphasizing their involvement in processes such as tumor growth, metastasis, immune modulation, and chemotherapy resistance. In addition, we discuss the challenges in isolating and characterizing sEVs. The review also highlights recent advances in the utilization of sEV-derived biomarkers for the early diagnosis, prognosis, and monitoring of pancreatic cancer. By synthesizing the latest findings, we aim to underscore the significance of sEVs in pancreatic cancer and their potential to revolutionize patient management through improved diagnostics and targeted therapies.
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Affiliation(s)
- Reaid Hasan
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Zhen Zhao
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Yuanke Li
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Yanli Liu
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Yuanyuan Zhang
- Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, NC, USA
| | - Kun Cheng
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA.
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2
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Rahimian S, Mirkazemi K, Kamalinejad A, Doroudian M. Exosome-based advances in pancreatic cancer: The potential of mesenchymal stem cells. Crit Rev Oncol Hematol 2025; 207:104594. [PMID: 39732301 DOI: 10.1016/j.critrevonc.2024.104594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 11/28/2024] [Accepted: 12/08/2024] [Indexed: 12/30/2024] Open
Abstract
Pancreatic cancer, especially pancreatic ductal adenocarcinoma (PDAC), is one of the most challenging clinical conditions due to its late-stage diagnosis and poor survival rates. Mesenchymal stem cells (MSCs), used for targeted therapies, are being explored as a promising treatment because of their tumor-homing properties and potential contributions to the pancreatic cancer microenvironment. Understanding these interactions is crucial for developing effective treatments. In this study, we investigated how MSCs exhibit tropism towards tumors, influence the microenvironment through paracrine effects, and serve as potential drug delivery vehicles. We also examined their role in progression and therapeutic resistance in pancreatic cancer therapy. The cytotoxic effects of certain compounds on tumor cells, the use of genetically modified MSCs as drug carriers, and the potential of exosomal biomarkers like miRNAs and riRNAs for diagnosis and monitoring of pancreatic cancer were analyzed. Overall, MSC-based therapies, coupled with insights into tumor-stromal interactions, offer new avenues for improving outcomes in pancreatic cancer treatment. Additionally, the use of MSC-based therapies in clinical trials is discussed. While MSCs show promising potential for pancreatic cancer monitoring, diagnosis, and treatment, results so far have been limited.
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Affiliation(s)
- Sana Rahimian
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Kimia Mirkazemi
- Faculty of Science, University of Amsterdam, Amsterdam, the Netherlands
| | - Armita Kamalinejad
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Mohammad Doroudian
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.
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3
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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.
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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
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4
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Moni ZA, Hasan Z, Alam MS, Roy N, Islam F. Diagnostic and Prognostic Significance of Exosomes and Their Components in Patients With Cancers. Cancer Med 2025; 14:e70569. [PMID: 39757782 DOI: 10.1002/cam4.70569] [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: 05/21/2024] [Revised: 12/15/2024] [Accepted: 12/21/2024] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND Cancer is the second leading cause of human mortality worldwide. Extracellular vesicles (EVs) from liquid biopsy samples are used in early cancer detection, characterization, and surveillance. Exosomes are a subset of EVs produced by all cells and present in all body fluids. They play an important role in the development of cancer because they are active transporters capable of carrying the contents of any type of cell. The objective of this review was to provide a brief overview of the clinical implication of exosomes or exosomal components in cancer diagnosis and prognosis. METHODS An extensive review of the current literature of exosomes and their components in cancer diagnosis and prognosis were carried out in the current study. RESULTS Tumor cells release exosomes that contribute to the formation of the pre-metastatic microenvironment, angiogenesis, invasion, and treatment resistance. On the contrary, tumor cells release more exosomes than normal cells, and these tumor-specific exosomes can carry the genomic and proteomic signature contents of the tumor cells, which can act as tools for the diagnosis and prognosis of patients with cancers. CONCLUSION This information may help clinicians to improve the management of cancer patients in clinical settings in the future.
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Affiliation(s)
- Zinnat Ara Moni
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh
| | - Zahid Hasan
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh
| | - Md Shaheen Alam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh
| | - Nitai Roy
- Department of Biochemistry and Molecular Biology, Patuakhali Science and Technology University, Patuakhali, Bangladesh
| | - Farhadul Islam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh
- School of Medicine and Dentistry, Griffith University, Gold Coast, Queensland, Australia
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5
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Li Y, Fei H, Xiao Z, Lu X, Zhang H, Liu M. Comprehensive analysis of EphA2 in pan-cancer: A prognostic biomarker associated with cancer immunity. Clin Exp Pharmacol Physiol 2024; 51:e13902. [PMID: 38886133 DOI: 10.1111/1440-1681.13902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 05/02/2024] [Accepted: 05/14/2024] [Indexed: 06/20/2024]
Abstract
BACKGROUND Several studies have reported a significant relationship between Ephrin receptor A2 (EphA2) and malignant progression in numerous cancers. However, there is a lack of comprehensive pan-cancer analysis on the prognostic value, mutation status, methylation landscape, and potential immunological function of EphA2. METHOD Using The Cancer Genome Atlas, Genotype Tissue Expression Database and GEO data, we analysed the differences in EphA2 expression between normal and tumour tissues and the effects of EphA2 on the prognosis of different tumours. Furthermore, using GSCALite, cBioPortal, TISDB, ULCLAN and TIMER 2.0 databases or platforms, we comprehensively analysed the potential oncogenic mechanisms or manifestations of EphA2 in 33 different tumour types, including tumour mutation status, DNA methylation status and immune cell infiltration. The correlation of EphA2 with immune checkpoints, tumour mutational burden, DNA microsatellite instability and DNA repair genes was also calculated. Finally, the effects of EphA2 inhibitors on the proliferation of human glioma and lung cancer cells were verified in cellular experiments. RESULTS EphA2 is differentially expressed in different tumours, and patients with overexpression have poorer overall survival. In addition, gene mutations, gene copy number variation and DNA/RNA methylation of EphA2 have been identified in various tumours. Moreover, EphA2 is positively associated with immune infiltration involving macrophages and CD8+ T cells. Further, EphA2 mRNA expression is significantly associated with immune checkpoint in various cancers, especially programmed death-ligand 1. Finally, the EphA2 inhibitor ALW-II-41-27 shows potent anti-tumour activity. CONCLUSION Our first pan-cancer study of EphA2 provides insight into the prognostic and immunological roles of EphA2 in different tumours, suggesting that EphA2 might be a potential biomarker for poor prognosis and immune infiltration in cancer.
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Affiliation(s)
- Yuchun Li
- Shenzhen Key Laboratory of Systems Medicine for inflammatory diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-sen University, Shenzhen, China
- Clinical Technology Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hanxiao Fei
- Shenzhen Key Laboratory of Systems Medicine for inflammatory diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-sen University, Shenzhen, China
| | - Zhiwen Xiao
- Department of Otolaryngology Head and Neck Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiuxia Lu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Hua Zhang
- Shenzhen Key Laboratory of Systems Medicine for inflammatory diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-sen University, Shenzhen, China
| | - Mengmeng Liu
- Department of Oncology, The Second Affiliated Hospital, Nanchang University, Nanchang, China
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6
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Zhou X, Yan Y, Shen Y, Xu M, Xu W. Exosomes: Emerging Insights into the Progression of Pancreatic Cancer. Int J Biol Sci 2024; 20:4098-4113. [PMID: 39113699 PMCID: PMC11302877 DOI: 10.7150/ijbs.97076] [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: 04/08/2024] [Accepted: 07/16/2024] [Indexed: 08/10/2024] Open
Abstract
Pancreatic cancer is a very aggressive and fatal malignancy with few therapeutic choices and a poor prognosis. Understanding the molecular pathways that drive its growth is critical for developing effective therapeutic strategies. Exosomes, small extracellular vesicles secreted by numerous cell types, have recently emerged as essential intercellular communication mediators, with implications for tumor growth and metastasis. In this article, we present a review of current knowledge about exosomes and their role in pancreatic cancer progression We discuss the biogenesis and characteristics of exosomes, as well as their cargo and functional significance in tumor growth, immune evasion, angiogenesis, invasion, and metastasis. We further emphasize the potential of exosomes as diagnostic biomarkers and therapeutic targets for pancreatic cancer. Finally, we discuss the challenges and future perspectives in using exosomes to improve patient outcomes in pancreatic cancer.
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Affiliation(s)
- Xulin Zhou
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Yongmin Yan
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213000, China
| | - Ye Shen
- Department of Hepatobiliary Pancreas Surgery, Aoyang Hospital Affiliated to Jiangsu University, Suzhou, 215000, China
| | - Min Xu
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Wenrong Xu
- Jiangsu University School of Medicine, Jiangsu University, Zhenjiang 212001, China
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7
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Qin C, Li T, Lin C, Zhao B, Li Z, Zhao Y, Wang W. The systematic role of pancreatic cancer exosomes: distant communication, liquid biopsy and future therapy. Cancer Cell Int 2024; 24:264. [PMID: 39054529 PMCID: PMC11271018 DOI: 10.1186/s12935-024-03456-5] [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: 05/02/2024] [Accepted: 07/18/2024] [Indexed: 07/27/2024] Open
Abstract
Pancreatic cancer remains one of the most lethal diseases worldwide. Cancer-derived exosomes, benefiting from the protective role of the lipid membrane, exhibit remarkable stability in the circulatory system. These exosomes, released by tumor microenvironment, contain various biomolecules such as proteins, RNAs, and lipids that plays a pivotal role in mediating distant communication between the local pancreatic tumor and other organs or tissues. They facilitate the transfer of oncogenic factors to distant sites, contributing to the compromised body immune system, distant metastasis, diabetes, cachexia, and promoting a microenvironment conducive to tumor growth and metastasis in pancreatic cancer patients. Beyond their intrinsic roles, circulating exosomes in peripheral blood can be detected to facilitate accurate liquid biopsy. This approach offers a novel and promising method for the diagnosis and management of pancreatic cancer. Consequently, circulating exosomes are not only crucial mediators of systemic cell-cell communication during pancreatic cancer progression but also hold great potential as precise tools for pancreatic cancer management and treatment. Exosome-based liquid biopsy and therapy represent promising advancements in the diagnosis and treatment of pancreatic cancer. Exosomes can serve as drug delivery vehicles, enhancing the targeting and efficacy of anticancer treatments, modulating the immune system, and facilitating gene editing to suppress tumor growth. Ongoing research focuses on biomarker identification, drug delivery systems, and clinical trials to validate the safety and efficacy of exosome-based therapies, offering new possibilities for early diagnosis and precision treatment in pancreatic cancer. Leveraging the therapeutic potential of exosomes, including their ability to deliver targeted drugs and modulate immune responses, opens new avenues for innovative treatment strategies.
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Affiliation(s)
- Cheng Qin
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tianyu Li
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chen Lin
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bangbo Zhao
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zeru Li
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yutong Zhao
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weibin Wang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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8
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Li D, Weng S, Zeng K, Xu H, Wang W, Shi J, Chen J, Chen C. Long non-coding RNAs and tyrosine kinase-mediated drug resistance in pancreatic cancer. Gene 2024; 895:148007. [PMID: 37981080 DOI: 10.1016/j.gene.2023.148007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 10/23/2023] [Accepted: 11/15/2023] [Indexed: 11/21/2023]
Abstract
Pancreatic cancer (PC) is one of the most malignant tumors with a dismal survival rate, this is primarily due to inevitable chemoresistance. Dysfunctional tyrosine kinases (TKs) and long non-coding RNAs (lncRNAs) affect the drug resistance and prognosis of PC. Here, we summarize the mechanisms by which TKs or lncRNAs mediate drug resistance and other malignant phenotypes. We also discuss that lncRNAs play oncogenic or tumor suppressor roles and different mechanisms including lncRNA-proteins/microRNAs to mediate drug resistance. Furthermore, we highlight that lncRNAs serve as upstream regulators of TKs mediating drug resistance. Finally, we display the clinical significance of TKs (AXL, EGFR, IGF1R, and MET), clinical trials, and lncRNAs (LINC00460, PVT1, HIF1A-AS1). In the future, TKs and lncRNAs may become diagnostic and prognostic biomarkers or drug targets to overcome the drug resistance of PC.
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Affiliation(s)
- Dangran Li
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China; The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing 210029, China
| | - Shiting Weng
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China; State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
| | - Kai Zeng
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China
| | - Hanmiao Xu
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China
| | - Wenyueyang Wang
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China
| | - Jinsong Shi
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China.
| | - Jinghua Chen
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China.
| | - Chen Chen
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China.
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Sahoo RK, Tripathi SK, Biswal S, Panda M, Mathapati SS, Biswal BK. Transforming native exosomes to engineered drug vehicles: A smart solution to modern cancer theranostics. Biotechnol J 2024; 19:e2300370. [PMID: 38375578 DOI: 10.1002/biot.202300370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 12/13/2023] [Accepted: 12/22/2023] [Indexed: 02/21/2024]
Abstract
Exosomes have been the hidden treasure of the cell in terms of cellular interactions, transportation and therapy. The native exosomes (NEx) secreted by the parent cells hold promising aspects in cancer diagnosis and therapy. NEx has low immunogenicity, high biocompatibility, low toxicity and high stability which enables them to be an ideal prognostic biomarker in cancer diagnosis. However, due to heterogeneity, NEx lacks specificity and accuracy to be used as therapeutic drug delivery vehicle in cancer therapy. Transforming these NEx with their innate structure and multiple receptors to engineered exosomes (EEx) can provide better opportunities in the field of cancer theranostics. The surface of the NEx exhibits numeric receptors which can be modified to pave the direction of its therapeutic drug delivery in cancer therapy. Through surface membrane, EEx can be modified with increased drug loading potentiality and higher target specificity to act as a therapeutic nanocarrier for drug delivery. This review provides insights into promising aspects of NEx as a prognostic biomarker and drug delivery tool along with its need for the transformation to EEx in cancer theranostics. We have also highlighted different methods associated with NEx transformations, their nano-bio interaction with recipient cells and major challenges of EEx for clinical application in cancer theranostics.
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Affiliation(s)
- Rajeev Kumar Sahoo
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, India
| | - Surya Kant Tripathi
- Lineberger Comprehensive Cancer Centre, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Stuti Biswal
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, India
| | - Munmun Panda
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, India
| | - Santosh S Mathapati
- Translational Health Science and Technology Institute Faridabad, Faridabad, Haryana, India
| | - Bijesh Kumar Biswal
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, India
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10
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Xie J, Zheng Z, Tuo L, Deng X, Tang H, Peng C, Zou Y. Recent advances in exosome-based immunotherapy applied to cancer. Front Immunol 2023; 14:1296857. [PMID: 38022585 PMCID: PMC10662326 DOI: 10.3389/fimmu.2023.1296857] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
Cancer stands as a prominent contributor to global mortality rates, necessitating immediate attention toward the exploration of its treatment options. Extracellular vesicles have been investigated as a potential cancer therapy in recent years. Among them, exosomes, as cell-derived nanovesicles with functions such as immunogenicity and molecular transfer, offer new possibilities for immunotherapy of cancer. However, multiple studies have shown that exosomes of different cellular origins have different therapeutic effects. The immunomodulatory effects of exosomes include but are not limited to inhibiting or promoting the onset of immune responses, regulating the function of molecular signaling pathways, and serving as carriers of antitumor drugs. Therefore, this mini-review attempts to summarize and evaluate the development of strategies for using exosomes to package exogenous cargos to promote immunotherapy in cancer.
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Affiliation(s)
- Jindong Xie
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Zihan Zheng
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Ling Tuo
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Xinpei Deng
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Hailin Tang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yutian Zou
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
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11
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Sato S, Nakagawa M, Terashima T, Morinaga S, Miyagi Y, Yoshida E, Yoshimura T, Seiki M, Kaneko S, Ueno M, Yamashita T, Koshikawa N. EphA2 Proteolytic Fragment as a Sensitive Diagnostic Biomarker for Very Early-stage Pancreatic Ductal Carcinoma. CANCER RESEARCH COMMUNICATIONS 2023; 3:1862-1874. [PMID: 37712876 PMCID: PMC10503484 DOI: 10.1158/2767-9764.crc-23-0087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 05/17/2023] [Accepted: 08/21/2023] [Indexed: 09/16/2023]
Abstract
Cleavage of erythropoietin-producing hepatocellular ephrin receptor A2 (EphA2) triggers malignant progression and yields an N-terminal fragment (EphA2-NF) detectable in sera from patients with pancreatic ductal carcinoma. We established a quantitative automated chemiluminescence immunoassay for EphA2-NF and evaluated serum EphA2-NF levels as a biomarker to diagnose pancreatic ductal carcinoma in the test and validation cohorts. The EphA2-NF value was elevated (above the cutoff: mean ± SD) in more than half of the patients with stage I/II pancreatic ductal carcinoma. Among patients receiving standard chemotherapy for pancreatic ductal carcinoma [gemcitabine plus nab-paclitaxel (GnP)], the median survival time of patients with elevated serum EphA2-NF was half that of patients with values below the cutoff. Patients with intraductal papillary mucinous neoplasm (IPMN), a precancerous pancreatic ductal carcinoma lesion, also show high serum EphA2 levels, which are associated with an increase in pancreatic duct size and the development of pancreatic ductal carcinoma in some cases. IHC showed loss of EphA2-NF staining in IPMN with pancreatic ductal carcinoma, but not in the normal epithelium or IPMN without pancreatic ductal carcinoma, regardless of the histologic grade. These results suggest that EphA2 cleavage is an essential event that occurs very early in pancreatic ductal carcinoma development, and that the consequent release of EphA2-NF can be detected in the serum. Thus, serum EphA2-NF could be a diagnostic biomarker for very early-stage pancreatic ductal carcinoma and pancreatic ductal carcinoma development from high-risk IPMN and as a prognostic biomarker after chemotherapy with GnP. SIGNIFICANCE EphA2 N-terminus deletion is involved in pancreatic ductal carcinoma development from high-risk IPMN and EphA2-NF produced by cleavage can be used as a serum biomarker to diagnose pancreatic ductal carcinoma and predict pancreatic ductal carcinoma development from high-risk IPMN.
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Affiliation(s)
- Shinya Sato
- Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan
- Department of Pathology, Kanagawa Cancer Center Hospital, Yokohama, Japan
- Morphological Analysis Laboratory, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Masatoshi Nakagawa
- Research and Development, Abbott Japan LLC, Chiba, Japan
- Department of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan
| | - Takeshi Terashima
- Advanced Preventive Medical Sciences Research Center, Kanazawa University Hospital, Kanazawa, Japan
| | - Soichiro Morinaga
- Department of Gastroenterological Surgery, Kanagawa Cancer Center Hospital, Yokohama, Japan
| | - Yohei Miyagi
- Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan
- Department of Pathology, Kanagawa Cancer Center Hospital, Yokohama, Japan
| | - Eisaku Yoshida
- Morphological Analysis Laboratory, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Toru Yoshimura
- Morphological Analysis Laboratory, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Motoharu Seiki
- Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Shuichi Kaneko
- Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Makoto Ueno
- Department of Gastroenterology, Kanagawa Cancer Center Hospital, Yokohama, Japan
| | - Taro Yamashita
- Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Naohiko Koshikawa
- Department of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan
- Clinical Cancer Proteomics Laboratory, Kanagawa Cancer Center Research Institute, Yokohama, Japan
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12
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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.
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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
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13
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Lucotti S, Kenific CM, Zhang H, Lyden D. Extracellular vesicles and particles impact the systemic landscape of cancer. EMBO J 2022; 41:e109288. [PMID: 36052513 PMCID: PMC9475536 DOI: 10.15252/embj.2021109288] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 02/16/2022] [Accepted: 03/23/2022] [Indexed: 11/09/2022] Open
Abstract
Intercellular cross talk between cancer cells and stromal and immune cells is essential for tumor progression and metastasis. Extracellular vesicles and particles (EVPs) are a heterogeneous class of secreted messengers that carry bioactive molecules and that have been shown to be crucial for this cell-cell communication. Here, we highlight the multifaceted roles of EVPs in cancer. Functionally, transfer of EVP cargo between cells influences tumor cell growth and invasion, alters immune cell composition and function, and contributes to stromal cell activation. These EVP-mediated changes impact local tumor progression, foster cultivation of pre-metastatic niches at distant organ-specific sites, and mediate systemic effects of cancer. Furthermore, we discuss how exploiting the highly selective enrichment of molecules within EVPs has profound implications for advancing diagnostic and prognostic biomarker development and for improving therapy delivery in cancer patients. Altogether, these investigations into the role of EVPs in cancer have led to discoveries that hold great promise for improving cancer patient care and outcome.
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Affiliation(s)
- Serena Lucotti
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - Candia M Kenific
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - Haiying Zhang
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - David Lyden
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
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14
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Exosome-Mediated Immunosuppression in Tumor Microenvironments. Cells 2022; 11:cells11121946. [PMID: 35741075 PMCID: PMC9221707 DOI: 10.3390/cells11121946] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 06/13/2022] [Accepted: 06/14/2022] [Indexed: 12/12/2022] Open
Abstract
Exosomes are membranous structures secreted by nearly all cell types. As critical messengers for intercellular communication, exosomes deliver bioactive cargoes to recipient cells and are involved in multiple physiopathological processes, including immunoregulation. Our pioneering study revealed that cancer cells release programmed death-ligand 1-positive exosomes into the circulation to counter antitumor immunity systemically via T cells. Tumor cell-derived exosomes (TDEs) also play an immunosuppressive role in other immunocytes, including dendritic cells (DCs), macrophages, natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs). Moreover, exosomes secreted by nontumor cells in the tumor microenvironments (TMEs) also exert immunosuppressive effects. This review systematically provides a summary of the immunosuppression induced by exosomes in tumor microenvironments, which modulates tumor growth, invasion, metastasis, and immunotherapeutic resistance. Additionally, therapeutic strategies targeting the molecular mechanism of exosome-mediated tumor development, which may help overcome several obstacles, such as immune tolerance in oncotherapy, are also discussed. Detailed knowledge of the specific functions of exosomes in antitumor immunity may contribute to the development of innovative treatments.
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15
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Cheng J, Wang X, Yuan X, Liu G, Chu Q. Emerging roles of exosome-derived biomarkers in cancer theranostics: messages from novel protein targets. Am J Cancer Res 2022; 12:2226-2248. [PMID: 35693088 PMCID: PMC9185602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Accepted: 04/14/2022] [Indexed: 06/15/2023] Open
Abstract
Effective biomarkers that guide therapeutics with limited adverse effects, have emerged as attractive research topics in cancer diagnosis and treatment. Cancer-derived exosomes, a type of extracellular vesicles representing molecular signatures of cells of origin, could serve as stable reservoirs for potential biomarkers (i.e., proteins, nucleic acids) in non-invasive cancer diagnosis and prognosis. In this review, the physiological and pathological roles of exosomes and their protein components in facilitating tumorigenesis are highlighted. Exosomes carrying proteins can participate in tumor development and progression through multiple signaling pathways, including EMT, invasion and metastasis. Meanwhile, the practical applications of exosomal proteins in detecting and monitoring several solid-tumor cancers (including lung, breast, pancreatic, colorectal and prostate cancers) were also summarized. More clinically relevant, exosomal proteins play pivotal roles in transmitting oncogenic potential or resistance to therapies in recipient cells, which might further support therapeutic strategy determinations.
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Affiliation(s)
- Jiongjia Cheng
- Key Laboratory of Advanced Functional Materials of Nanjing, Nanjing Xiaozhuang UniversityNanjing 211171, Jiangsu, China
| | - Xiaofeng Wang
- Key Laboratory of Advanced Functional Materials of Nanjing, Nanjing Xiaozhuang UniversityNanjing 211171, Jiangsu, China
| | - Xuechun Yuan
- Department of Medicinal Chemistry, China Pharmaceutical UniversityNanjing 211198, Jiangsu, China
| | - Guangxiang Liu
- Key Laboratory of Advanced Functional Materials of Nanjing, Nanjing Xiaozhuang UniversityNanjing 211171, Jiangsu, China
| | - Qian Chu
- Department of Medicinal Chemistry, China Pharmaceutical UniversityNanjing 211198, Jiangsu, China
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16
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Romano R, Picca A, Eusebi LHU, Marzetti E, Calvani R, Moro L, Bucci C, Guerra F. Extracellular Vesicles and Pancreatic Cancer: Insights on the Roles of miRNA, lncRNA, and Protein Cargos in Cancer Progression. Cells 2021; 10:1361. [PMID: 34205944 PMCID: PMC8226820 DOI: 10.3390/cells10061361] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 05/28/2021] [Accepted: 05/29/2021] [Indexed: 01/18/2023] Open
Abstract
Pancreatic cancer (PC) is among the most devastating digestive tract cancers worldwide. This cancer is characterized by poor diagnostic detection, lack of therapy, and difficulty in predicting tumorigenesis progression. Although mutations of key oncogenes and oncosuppressor involved in tumor growth and in immunosurveillance escape are known, the underlying mechanisms that orchestrate PC initiation and progression are poorly understood or still under debate. In recent years, the attention of many researchers has been concentrated on the role of extracellular vesicles and of a particular subset of extracellular vesicles, known as exosomes. Literature data report that these nanovesicles are able to deliver their cargos to recipient cells playing key roles in the pathogenesis and progression of many pancreatic precancerous conditions. In this review, we have summarized and discussed principal cargos of extracellular vesicles characterized in PC, such as miRNAs, lncRNAs, and several proteins, to offer a systematic overview of their function in PC progression. The study of extracellular vesicles is allowing to understand that investigation of their secretion and analysis of their content might represent a new and potential diagnostic and prognostic tools for PC.
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Affiliation(s)
- Roberta Romano
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy;
| | - Anna Picca
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (E.M.); (R.C.)
- Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institute and Stockholm University, 171 77 Stockholm, Sweden
| | - Leonardo Henry Umberto Eusebi
- Gastroenterology and Endoscopy Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Gastroenterology and Endoscopy Unit, Sant’Orsola University Hospital, 40138 Bologna, Italy
| | - Emanuele Marzetti
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (E.M.); (R.C.)
- Institute of Internal Medicine and Geriatrics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Riccardo Calvani
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (E.M.); (R.C.)
- Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institute and Stockholm University, 171 77 Stockholm, Sweden
| | - Loredana Moro
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA; or
- Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, 70126 Bari, Italy
| | - Cecilia Bucci
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy;
| | - Flora Guerra
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy;
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