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Dai X, Huang H, Liu F. Rapid Identification of Esophageal Squamous Cell Carcinoma Biomarkers by MALDI-TOF MS Fingerprinting of Extracellular Vesicles. Anal Chem 2025. [PMID: 40326690 DOI: 10.1021/acs.analchem.4c06273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/07/2025]
Abstract
Esophageal cancer is a major global health challenge, with high incidence and mortality due to the lack of rapid and sensitive diagnostic tools and specific biomarkers. Cancer-cell-derived extracellular vesicles (EVs) carry unique proteins and nucleic acids, making them valuable sources of cancer biomarkers. We report an integrated method that combines an ultrafast exosome isolation system (EXODUS) with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) to detect EVs and identify protein biomarkers for diagnosing and monitoring esophageal squamous cell carcinoma (ESCC). EVs derived from 20 mL culture medium supernatant of ESCC cells with varying degrees of differentiation serve as analysis models. We use EXODUS to isolate EVs rapidly. We then analyze the intact EVs using MALDI-TOF MS, which provides cell line-specific EV fingerprints in minutes. These protein fingerprints allow the discrimination of ESCC from normal control cells and enable the classification of ESCC based on the degree of cell differentiation. We explore critical EV biomarker peaks for ESCC diagnosis (5555 m/z, 8603 m/z, etc.) and monitoring (2268 m/z, etc.). Potential EV biomarker candidates, including YBX1, DIRAS2, HIST1H2AH, and MYBBP1A, are identified through tandem mass tag (TMT) proteomics. We tentatively assign the protein identities of EV marker peaks by correlation with the TMT proteomics. Applying this method to plasma-derived EVs shows promise for rapid, minimally invasive diagnosis and monitoring of ESCC.
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Affiliation(s)
- Xiaodan Dai
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Huiying Huang
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Fei Liu
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
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2
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Wang C, Shi ZZ. Exosomes in esophageal cancer: function and therapeutic prospects. Med Oncol 2024; 42:18. [PMID: 39601925 DOI: 10.1007/s12032-024-02543-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 10/15/2024] [Indexed: 11/29/2024]
Abstract
Esophageal cancer (EC) is one of the most common malignant tumors worldwide. Exosomes are a type of extracellular vesicles produced by eukaryotic cells and present in all body fluids. Recent studies have revealed that exosomes can be used as a tool for cell signaling and have great potential in cancer diagnosis and treatment strategies. This article reviews the research progress of exosomes in EC in recent years, mainly including the mechanism of action, diagnostic markers, therapeutic targets, and drug carriers. The challenges faced are discussed to provide guidelines for further research in future.
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Affiliation(s)
- Chong Wang
- Medical School, Kunming University of Science and Technology, Kunming, 650500, China
| | - Zhi-Zhou Shi
- Medical School, Kunming University of Science and Technology, Kunming, 650500, China.
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3
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Wu N, Cai J, Jiang J, Lin Y, Wang X, Zhang W, Kang M, Zhang P. Biomarkers of lymph node metastasis in esophageal cancer. Front Immunol 2024; 15:1457612. [PMID: 39399490 PMCID: PMC11466839 DOI: 10.3389/fimmu.2024.1457612] [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: 07/01/2024] [Accepted: 09/12/2024] [Indexed: 10/15/2024] Open
Abstract
Esophageal cancer (EC) is among the most aggressive malignancies, ranking as the seventh most prevalent malignant tumor worldwide. Lymph node metastasis (LNM) indicates localized spread of cancer and often correlates with a poorer prognosis, emphasizing the necessity for neoadjuvant systemic therapy before surgery. However, accurate identification of LNM in EC presents challenges due to the lack of satisfactory diagnostic techniques. Imaging techniques, including ultrasound and computerized tomography scans, have low sensitivity and accuracy in assessing LNM. Additionally, the existing serological detection lacks precise biomarkers. The intricate and not fully understood molecular processes involved in LNM of EC contribute to current detective limitations. Recent research has shown potential in using various molecules, circulating tumor cells (CTCs), and changes in the microbiota to identify LNM in individuals with EC. Through summarizing potential biomarkers associated with LNM in EC and organizing the underlying mechanisms involved, this review aims to provide insights that facilitate biomarker development, enhance our understanding of the underlying mechanisms, and ultimately address the diagnostic challenges of LNM in clinical practice.
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Affiliation(s)
| | | | | | | | | | | | - Mingqiang Kang
- Department of Thoracic Surgery, Fujian Medical University Union Hospital,
Fuzhou, China
| | - Peipei Zhang
- Department of Thoracic Surgery, Fujian Medical University Union Hospital,
Fuzhou, China
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4
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Yuan L, Ji H, Cao Y, Yi H, Leng Q, Zhou J, Mei X. Exosomes in esophageal cancer: Promising nanocarriers in cancer progression, diagnosis, prognosis, and therapy. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2024; 16:e1989. [PMID: 39217461 DOI: 10.1002/wnan.1989] [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: 03/03/2023] [Revised: 06/26/2024] [Accepted: 07/31/2024] [Indexed: 09/04/2024]
Abstract
Esophageal cancer (EC) is one of the most fatal cancers all over the world. Sensitive detection modalities for early-stage EC and efficient treatment methods are urgently needed for the improvement of the prognosis of EC. Exosomes are small vesicles for intercellular communication, mediating many biological responses including cancer progression, which are not only promising biomarkers for diagnosis and prognosis but also therapeutic tools for EC. This review provides an overview of the relationships between exosomes and EC progression, as well as the application of exosomes in the diagnosis, prognosis, and treatment of EC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
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Affiliation(s)
- Ligong Yuan
- Department of Thoracic Surgery, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Haoran Ji
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yang Cao
- Peking University Health Science Center, Peking University, Beijing, China
| | - Hang Yi
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qihao Leng
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Jie Zhou
- Department of Chemistry and Biochemistry, University of California San Diego, San Diego, California, USA
| | - Xinyu Mei
- Department of Thoracic Surgery, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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5
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Aksoy A, Varoglu A, Onalan EE, Tektemur A, Artas G, Koc M, Cakmak M, Aydin S, Kilic M, Ulas M. The knockdown of stathmin with si-RNA inhibits invasion of mesothelioma. Tissue Cell 2024; 87:102303. [PMID: 38244401 DOI: 10.1016/j.tice.2024.102303] [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: 06/07/2023] [Revised: 12/11/2023] [Accepted: 01/02/2024] [Indexed: 01/22/2024]
Abstract
BACKGROUND To investigate the mechanism of action of stathmin1 (STMN1) in mesothelioma (MSM) and whether it has any role in its treatment. METHODS STMN1 expression was examined using immunohistochemistry in biopsy tissues taken from MSM patients. The relationships between the levels of STMN1 expression in the pathology preparations of MSM patients, and the clinicopathological characteristics of these patients, and their survival times were investigated. Transfection of STMN1-specific siRNA into SPC212 cells was compared to negative control siRNAs. The mRNA levels of genes that may play a role in invasion, apoptosis, and autophagy were evaluated by RT-PCR. RESULTS The expression of STMN1 was shown to be high in MSM tissues (p < 0.05). It was found that the only independent predictor factor affecting the survival time of MSM patients was the disease stage (p < 0.05). STMN1 was significantly reduced after siRNA intervention (81.5%). STMN1 with specific siRNA has been shown to suppress invasion by reducing the mRNA levels of cadherin-6 (CDH6), fibroblast growth factor-8 (FGF8), hypoxia-inducible factor 1 (HIF1A), matrix metallopeptidase 1-2 (gelatinase A) (MMP1-2), and TIMP metallopeptidase inhibitor 2 (TIMP2), which are important markers for invasion. Although the expression of apoptosis and autophagy-related genes, caspase-2 (Casp2) and LC-3, was reduced by silencing STMN1 with specific siRNA in western blot analysis, this effect was not observed in PCR results. CONCLUSIONS Immunohistochemical analysis of STMN1 may contribute to the differential diagnosis of MSM, and STMN1 may also be considered as a potential therapeutic target in the early invasive stage of MSM therapy.
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Affiliation(s)
- Asude Aksoy
- Department of Medical Oncology, University of Health Sciences, Fethi Sekin City Hospital SUAM, Elazig, Turkey.
| | - Asuman Varoglu
- Department of Neurology, Medical Faculty, Medeniyet University, Istanbul, Turkey
| | - Ebru Etem Onalan
- Department of Medical Biology and Genetics, Firat University, Elazig, Turkey
| | - Ahmet Tektemur
- Department of Medical Biology and Genetics, Firat University, Elazig, Turkey
| | - Gokhan Artas
- Department of Pathology, Medical Faculty, Firat University, Elazig, Turkey
| | - Mustafa Koc
- Department of Radiology, Medical Faculty, Firat University, Elazig, Turkey
| | - Muharrem Cakmak
- Department of Thoracic Surgery, Medical Faculty, Firat University, Elazig, Turkey
| | - Siyami Aydin
- Department of Thoracic Surgery, Medical Faculty, Firat University, Elazig, Turkey
| | - Murat Kilic
- Department of Thoracic Surgery, Inonu University, Malatya, Turkey
| | - Mustafa Ulas
- Department of Physiology, Medical Faculty, Firat University, Elazig, Turkey
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Zong H, Shang X, Wang X, Chen T, Wang Y, Ren Y, Jiang Y, Li Y, Lv Q, Liu P. Diagnosis of septic shock by serum measurement of human neutrophil lipocalin by a rapid homogeneous assay. J Immunol Methods 2023; 522:113570. [PMID: 37774777 DOI: 10.1016/j.jim.2023.113570] [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: 05/23/2023] [Revised: 09/20/2023] [Accepted: 09/21/2023] [Indexed: 10/01/2023]
Abstract
BACKGROUND Human neutrophil lipocalin (HNL) is a marker of neutrophil activation and has a high efficacy in diagnosing bacterial infections. In this study, we applied the AlphaLISA technique to measure the serum level of HNL, evaluate HNL's efficacy in diagnosing septic shock, and identify any association between HNL level and septic patients' prognosis. METHODS We collected 146 serum samples from the Fifth Medical Center of Chinese PLA General Hospital. HNL was measured by AlphaLISA and results were compared with commercial ELISA kits. We studied 78 patients admitted to the ICU with sepsis and data on their clinical and physiological characteristics were recorded. Blood levels of HNL, procalcitonin (PCT), high-sensitivity C-reactive protein (hs-CRP), and lactate were measured. A receiver operating characteristic (ROC) curve was used to evaluate the performance of each marker. RESULTS The AlphaLISA assay for serum HNL had a detection range from 1.5 ng/mL to 1000 ng/mL, with a detection limit of 1 ng/mL and a detection time of approximately 25 min. The AlphaLISA assay's results were in high agreement with ELISA results (R2 = 0.9413). HNL levels were analyzed in sepsis patients, and HNL was significantly higher in sepsis patients with shock compared to sepsis patients without shock (median 356.47 ng/mL vs 158.93 ng/mL, P < 0.0001) and in the 28-day non-survivor group compared to the 28-day survivor group (median 331.83 ng/mL vs 175.17 ng/mL, P < 0.0001). ROC curve analysis was performed for the biomarkers. In differentiating the diagnosis of septic shock from sepsis patients, HNL was the most effective marker (AUC = 0.857), followed by PCT (AUC = 0.754) and hs-CRP (AUC = 0.627). In predicting the prognosis of septic patients, lactate had the best effect (AUC = 0.805), followed by HNL (AUC = 0.784), PCT (AUC = 0.721), and hs-CRP (AUC = 0.583). CONCLUSIONS As an assessment tool, we found that our AlphaLISA had good consistency with an ELISA and had several other advantages, including requiring a shorter processing time and detecting a wider range of serum HNL concentrations. Monitoring serum HNL levels of patients admitted to the ICU might be useful in distinguishing sepsis patients who have septic shock from other sepsis patients, indicating its value in the prediction of sepsis patient prognosis.
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Affiliation(s)
- Huijun Zong
- State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China; The Fifth School of Clinical Medicine, Anhui Medical University, Hefei 230032, China; Department of Critical Care Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China
| | - Xueyi Shang
- Department of Critical Care Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China
| | - Xin Wang
- Department of Critical Care Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China
| | - Ting Chen
- The Fifth School of Clinical Medicine, Anhui Medical University, Hefei 230032, China; Department of Critical Care Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China
| | - Ye Wang
- State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China
| | - Yuhao Ren
- State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China
| | - Yongqiang Jiang
- State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China
| | - Yan Li
- The Fifth School of Clinical Medicine, Anhui Medical University, Hefei 230032, China; Department of Critical Care Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China.
| | - Qingyu Lv
- State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China.
| | - Peng Liu
- State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China.
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Li Y, Wang JX, Yibi RH. Prediction of lymph node metastasis in early esophageal cancer. World J Gastrointest Surg 2023; 15:2294-2304. [PMID: 37969711 PMCID: PMC10642458 DOI: 10.4240/wjgs.v15.i10.2294] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 08/17/2023] [Accepted: 09/04/2023] [Indexed: 10/27/2023] Open
Abstract
BACKGROUND Given the poor prognosis of patients with lymph node metastasis, estimating the lymph node status in patients with early esophageal cancer is crucial. Indicators that could be used to predict lymph node metastasis in early esophageal cancer have been reported in many recent studies, but no recent studies have included a review of this subject. AIM To review indicators predicting lymph node metastasis in early esophageal squamous cell carcinoma (ESCC) and early esophageal adenocarcinoma (EAC). METHODS We searched PubMed with "[early esophageal cancer (Title/Abstract)] and [lymph node (Title/Abstract)]" or "[early esophageal carcinoma (Title/Abstract)] and [lymph node (Title/Abstract)]" or "[superficial esophageal cancer (Title/Abstract)] and [lymph node (Title/Abstract)]." A total of 29 studies were eligible for analysis. RESULTS Preoperative imaging (size), serum markers (microRNA-218), postoperative pathology and immunohistochemical analysis (depth of invasion, tumor size, differentiation grade, lymphovascular invasion, neural invasion, expression of PIM-1 < 30%) were predictive factors for lymph node metastasis in both early ESCC and EAC. Serum markers (thymidine kinase 1 ≥ 3.38 pmol/L; cytokeratin 19 fragment antigen 21-1 > 3.30 ng/mL; stathmin-1) and postoperative pathology and immunohistochemical analysis (overexpression of cortactin, mixed-lineage leukaemia 2, and stanniocalcin-1) were predictive for lymph node metastasis in early ESCC. Transcription of CD69, myeloid differentiation protein 88 and toll-like receptor 4 and low expression of olfactomedin 4 were predictive of lymph node metastasis in early EAC. A total of 6 comprehensive models for early ESCC, including logistic regression model, nomogram, and artificial neural network (ANN), were reviewed. The areas under the receiver operating characteristic curve of these models reached 0.789-0.938, and the ANN performed best. As all these models relied on postoperative pathology, further models focusing on serum markers, imaging and immunohistochemical indicators are still needed. CONCLUSION Various factors were predictive of lymph node metastasis in early esophageal cancer, and present comprehensive models predicting lymph node metastasis in early ESCC mainly relied on postoperative pathology. Further studies focusing on serum markers, imaging and immunohistochemical indicators are still in need.
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Affiliation(s)
- Yan Li
- Department of Gastroenterology, Lhasa People’s Hospital, Lhasa 850000, Tibet Autonomous Region, China
| | - Jun-Xiong Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100000, China
- National Clinical Research Center for Digestive Diseases, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing 100000, China
| | - Ran-Hen Yibi
- Department of Gastroenterology, Lhasa People’s Hospital, Lhasa 850000, Tibet Autonomous Region, China
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Liu R, Liang X, Guo H, Li S, Yao W, Dong C, Wu J, Lu Y, Tang J, Zhang H. STNM1 in human cancers: role, function and potential therapy sensitizer. Cell Signal 2023:110775. [PMID: 37331415 DOI: 10.1016/j.cellsig.2023.110775] [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: 04/19/2023] [Revised: 05/23/2023] [Accepted: 06/14/2023] [Indexed: 06/20/2023]
Abstract
STMN1 belongs to the stathmin gene family, it encodes a cytoplasmic phosphorylated protein, stathmin1, which is commonly observed in vertebrate cells. STMN1 is a structural microtubule-associated protein (MAP) that binds to microtubule protein dimers rather than microtubules, with each STMN1 binding two microtubule protein dimers and preventing their aggregation, leading to microtubule instability. STMN1 expression is elevated in a number of malignancies, and inhibition of its expression can interfere with tumor cell division. Its expression can change the division of tumor cells, thereby arresting cell growth in the G2/M phase. Moreover, STMN1 expression affects tumor cell sensitivity to anti-microtubule drug analogs, including vincristine and paclitaxel. The research on MAPs is limited, and new insights on the mechanism of STMN1 in different cancers are emerging. The effective application of STMN1 in cancer prognosis and treatment requires further understanding of this protein. Here, we summarize the general characteristics of STMN1 and outline how STMN1 plays a role in cancer development, targeting multiple signaling networks and acting as a downstream target for multiple microRNAs, circRNAs, and lincRNAs. We also summarize recent findings on the function role of STMN1 in tumor resistance and as a therapeutic target for cancer.
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Affiliation(s)
- Ruiqi Liu
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou Medical College, Hangzhou, Zhejiang, China; Graduate Department, Bengbu Medical College, Bengbu, Anhui, China
| | - Xiaodong Liang
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou Medical College, Hangzhou, Zhejiang, China; Graduate Department, Bengbu Medical College, Bengbu, Anhui, China
| | - Haiwei Guo
- Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital Hangzhou Medical College), Hangzhou, Zhejiang, China
| | - Shuang Li
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Weiping Yao
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou Medical College, Hangzhou, Zhejiang, China; Graduate Department, Bengbu Medical College, Bengbu, Anhui, China
| | - Chenfang Dong
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou Medical College, Hangzhou, Zhejiang, China; Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiajun Wu
- Graduate Department, Bengbu Medical College, Bengbu, Anhui, China; Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital Hangzhou Medical College), Hangzhou, Zhejiang, China
| | - Yanwei Lu
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Jianming Tang
- Department of Radiation Oncology, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Haibo Zhang
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou Medical College, Hangzhou, Zhejiang, China.
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Zhu Q, Xu H, Huang L, Luo J, Li H, Yang R, Liu X, Liu F. Identification and detection of plasma extracellular vesicles-derived biomarkers for esophageal squamous cell carcinoma diagnosis. Biosens Bioelectron 2023; 225:115088. [PMID: 36739741 DOI: 10.1016/j.bios.2023.115088] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/13/2023] [Accepted: 01/18/2023] [Indexed: 01/22/2023]
Abstract
Esophageal cancer is a malignant tumor with two-thirds of patients having a local recurrence or distant metastasis. To date, diagnostic biomarkers with high sensitivity and specificity are lacking. Extracellular vesicles (EVs) have shown their potential values as disease biomarkers as they carry specific proteins and RNAs derived from cancer cells. In this study, we investigate ESCC precision diagnostics from the insights of circulating EVs, and integrate the ultrafast EV isolation approach (EXODUS) and ELISA for fast detection and screening of ESCC patients. First, we isolate and characterize the high-purity plasma EVs with EXODUS and identify 401 proteins and 372 proteins from ESCC patient and healthy individuals, respectively. Further looking into the differentially expressed proteins (DEPs) of ESCC patients and enriched KEGG pathways, we discover EV-CD14 as a potential diagnostic biomarker for ESCC, which has been further validated as a significantly differentially expressed protein by Western Blot and immunogold labelling TEM. For fast screening and detection of ESCC towards clinical applications, we apply ELISA method to diagnose ESCC from 60 clinical samples based on circulating EV-CD14, which shows a high AUC value up to 96.0% for detection of ESCC in a test set (30 samples), and displays a high accuracy rate up to 90% for prediction of ESCC in a screening test (30 samples). Our results suggest that the circulating EV-CD14 may highly be related to the initiation and progression of ESCC, providing a novel method for the diagnosis and prognosis of ESCC towards clinical translations.
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Affiliation(s)
- Qingfu Zhu
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Hao Xu
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Liu Huang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Jiaxin Luo
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Hengrui Li
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Rui Yang
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Xiaoling Liu
- Center for Biological Science and Technology, Advanced Institute of Natural Sciences, Beijing Normal University at Zhuhai, Zhuhai, China
| | - Fei Liu
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
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10
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David P, Mittelstädt A, Kouhestani D, Anthuber A, Kahlert C, Sohn K, Weber GF. Current Applications of Liquid Biopsy in Gastrointestinal Cancer Disease-From Early Cancer Detection to Individualized Cancer Treatment. Cancers (Basel) 2023; 15:cancers15071924. [PMID: 37046585 PMCID: PMC10093361 DOI: 10.3390/cancers15071924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/20/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
Worldwide, gastrointestinal (GI) cancers account for a significant amount of cancer-related mortality. Tests that allow an early diagnosis could lead to an improvement in patient survival. Liquid biopsies (LBs) due to their non-invasive nature as well as low risk are the current focus of cancer research and could be a promising tool for early cancer detection. LB involves the sampling of any biological fluid (e.g., blood, urine, saliva) to enrich and analyze the tumor's biological material. LBs can detect tumor-associated components such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), and circulating tumor cells (CTCs). These components can reflect the status of the disease and can facilitate clinical decisions. LBs offer a unique and new way to assess cancers at all stages of treatment, from cancer screenings to prognosis to management of multidisciplinary therapies. In this review, we will provide insights into the current status of the various types of LBs enabling early detection and monitoring of GI cancers and their use in in vitro diagnostics.
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Affiliation(s)
- Paul David
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Anke Mittelstädt
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Dina Kouhestani
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Anna Anthuber
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Christoph Kahlert
- Department of Surgery, Carl Gustav Carus University Hospital, 01307 Dresden, Germany
| | - Kai Sohn
- Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, 70569 Stuttgart, Germany
| | - Georg F Weber
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, University Hospital of Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany
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11
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Zhao L, Yu L, Wang X, He J, Zhu X, Zhang R, Yang A. Mechanisms of function and clinical potential of exosomes in esophageal squamous cell carcinoma. Cancer Lett 2023; 553:215993. [PMID: 36328162 DOI: 10.1016/j.canlet.2022.215993] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 10/05/2022] [Accepted: 10/27/2022] [Indexed: 11/20/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) remains one of the most lethal and widespread malignancies in China. Exosomes, a subset of tiny extracellular vesicles manufactured by all cells and present in all body fluids, contribute to intercellular communication and have become a focus of the search for new therapeutic strategies for cancer. A number of global analyses of exosome-mediated functions and regulatory mechanism in malignant diseases have recently been reported. There is extensive evidence that exosomes can be used as diagnostic and prognostic markers for cancer. However, our understanding of their clinical value and mechanisms of action in ESCC is still limited and has not been systematically reviewed. Here, we review current research specifically focused on the functions and mechanisms of action of ESCC tumor-derived exosomes and non-ESCC-derived exosomes in ESCC progression and describe opportunities and challenges in the clinical translation of exosomes.
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Affiliation(s)
- Lijun Zhao
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Lili Yu
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Xiangpeng Wang
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Jangtao He
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Xiaofei Zhu
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
| | - Rui Zhang
- The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Angang Yang
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China; The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.
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12
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Shahverdi M, Darvish M. Exosomal microRNAs: A Diagnostic and Therapeutic Small Bio-molecule in Esophageal Cancer. Curr Mol Med 2023; 23:312-323. [PMID: 35319366 DOI: 10.2174/1566524022666220321125134] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 12/07/2021] [Accepted: 12/20/2021] [Indexed: 02/08/2023]
Abstract
Esophageal cancer (EC) is one of the major causes of cancer-related death worldwide. EC is usually diagnosed at a late stage, and despite aggressive therapy, the five-year survival rate of patients remains poor. Exosomes play important roles in cancer biology. Indeed, exosomes are implicated in tumor proliferation, angiogenesis, and invasion. They contain bioactive molecules such as lipids, proteins, and non-coding RNAs. Exosome research has recently concentrated on microRNAs, which are tiny noncoding endogenous RNAs that can alter gene expression and are linked to nearly all physiological and pathological processes, including cancer. It is suggested that deregulation of miRNAs results in cancer progression and directly induces tumor initiation. In esophageal cancer, miRNA dysregulation plays an important role in cancer prognosis and patients' responsiveness to therapy, indicating that miRNAs are important in tumorigenesis. In this review, we summarize the impact of exosomal miRNAs on esophageal cancer pathogenesis and their potential applications for EC diagnosis and therapy.
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Affiliation(s)
- Mahshid Shahverdi
- Department of Medical Biotechnology, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Maryam Darvish
- Department of Medical Biotechnology, School of Medicine, Arak University of Medical Sciences, Arak, Iran
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13
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Liu S, Zheng Q, Zhang R, Li T, Zhan J. Construction of a combined random forest and artificial neural network diagnosis model to screening potential biomarker for hepatoblastoma. Pediatr Surg Int 2022; 38:2023-2034. [PMID: 36271952 DOI: 10.1007/s00383-022-05255-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/19/2022] [Indexed: 11/28/2022]
Abstract
PURPOSE The purpose of our study is to identify potential biomarkers of hepatoblastoma (HB) and further explore the pathogenesis of it. METHODS Differentially expressed genes (DEGs) were incorporated into the combined random forest and artificial neural network diagnosis model to screen candidate genes for HB. Gene set enrichment analysis (GSEA) was used to analyze the ARHGEF2. Student's t test was performed to evaluate the difference of tumor-infiltrating immune cells (TIICs) between normal and HB samples. Spearson correlation analysis was used to calculate the correlation between ARHGEF2 and TIICs. RESULTS ARHGEF2, TCF3, TMED3, STMN1 and RAVER2 were screened by the new model. The GSEA of ARHGEF2 included cell cycle pathway and antigen processing presenting pathway. There were significant differences in the composition of partial TIICs between HB and normal samples (p < 0.05). ARHGEF2 was significantly correlated with memory B cells (Cor = 0.509, p < 0.05). CONCLUSION These 5 candidate genes contribute to the molecular diagnosis and targeted therapy of HB. And we found "ARHGEF2-RhoA-Cyclin D1/CDK4/CDK6-EF2" is a key mechanism regulating cell cycle pathway in HB. This will be helpful in the treatment of HB. The occurrence of HB is related to abnormal TIICs. We speculated that memory B cells play an important role in HB.
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Affiliation(s)
- Shaowen Liu
- Clinical School of Paediatrics, Tianjin Medical University, 238 Longyan Road, Beichen District, Tianjin, 300400, China
| | - Qipeng Zheng
- Clinical School of Paediatrics, Tianjin Medical University, 238 Longyan Road, Beichen District, Tianjin, 300400, China
| | - Ruifeng Zhang
- Clinical School of Paediatrics, Tianjin Medical University, 238 Longyan Road, Beichen District, Tianjin, 300400, China
| | - Tengfei Li
- Clinical School of Paediatrics, Tianjin Medical University, 238 Longyan Road, Beichen District, Tianjin, 300400, China
| | - Jianghua Zhan
- Clinical School of Paediatrics, Tianjin Medical University, 238 Longyan Road, Beichen District, Tianjin, 300400, China. .,Tianjin Children's Hospital, 238 Longyan Road, Beichen District, Tianjin, 300400, China.
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Yang L, Salai A, Sun X, Liu Q, Liu T, Zhang Q, Tuerxun A, Tan Y, Zheng S, Lu X. Proteomic profiling of plasma exosomes reveals CD82 involvement in the development of esophageal squamous cell carcinoma. J Proteomics 2022; 265:104662. [PMID: 35728771 DOI: 10.1016/j.jprot.2022.104662] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 05/30/2022] [Accepted: 06/07/2022] [Indexed: 02/07/2023]
Abstract
The Xinjiang Uygur autonomous region has a high incidence of esophageal cancer. For the early diagnosis of patients with esophageal squamous cell carcinoma (ESCC), exosomes were isolated and quantified by liquid chromatography tandem mass spectrometry ((LC-MS/MS) with data independent acquisition (DIA) from the peripheral blood of patients with benign esophageal disease (BED), esophageal intraepithelial neoplasia (EIN) and ESCC. A total of 1117 proteins were identified in the above 9 samples. The proteomic results showed that the quantity of CD82 in exosomes of EIN was significantly higher than that in patients with BED and ESCC. Meanwhile, our ELISA test verified our proteomic results. In addition, the immunohistochemical results showed high CD82 expression in adjacent normal tissues and low expression in ESCC tissues. CD82 expression in ESCC tissues was negatively correlated with tumor stage and the expression of PKM2, and the high expression of CD82 combined with low expression of PKM2 in ESCC tissues suggested a good prognosis. To further clarify the tumor suppressive mechanism of CD82, the TIMER and TISDB databases were analyzed, and CD82 expression in tumor tissues was found to be related to the infiltration of immune cells. CD82 in exosomes is involved in the development of ESCC. SIGNIFICANCE: Xinjiang is a high incidence area of ESCC. When diagnosed in the middle and late stages of the disease, the prognosis of patients is poor. Exosomes provide the possibility of relatively noninvasive and early detection of esophageal carcinogenesis. To the best of our knowledge, this was the first study using the DIA technique to analyze the exosomal proteins of patients with different stages of ESCC. The proteins identified in the exosomes in these three groups could provide insights for understanding how exosomes promote the occurrence of ESCC, the antitumour mechanism of humans and the early diagnosis of ESCC.
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Affiliation(s)
- Lifei Yang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830000, China; First Department of Lung Cancer Chemotherapy, Cancer Hospital Affiliated of Xinjiang Medical University, Urumqi 830000, China
| | - Adili Salai
- Second Ward of Thoracic Surgery, Cancer Hospital Affiliated of Xinjiang Medical University, Urumqi 830000, China
| | - Xiaohong Sun
- First Ward of Thoracic Surgery, Cancer Hospital Affiliated of Xinjiang Medical University, Urumqi 830000, China
| | - Qing Liu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830000, China
| | - Tao Liu
- Department of Clinical Laboratory, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830000, China
| | - Qiqi Zhang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830000, China
| | - Aerziguli Tuerxun
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830000, China
| | - Yiyi Tan
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830000, China
| | - Shutao Zheng
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830000, China.
| | - Xiaomei Lu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830000, China.
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Zhu Q, Huang L, Yang Q, Ao Z, Yang R, Krzesniak J, Lou D, Hu L, Dai X, Guo F, Liu F. Metabolomic analysis of exosomal-markers in esophageal squamous cell carcinoma. NANOSCALE 2021; 13:16457-16464. [PMID: 34648610 DOI: 10.1039/d1nr04015d] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a worldwide malignancy with high mortality rates and poor prognosis due to the lack of effective biomarkers for early detection. Exosomes have been extensively explored as attractive biomarkers for cancer diagnosis and treatment. However, little is known about exosome metabolomics and their roles in ESCC. Here, we performed a targeted metabolomic analysis of plasma exosomes and identified 196 metabolites, mainly including lipid fatty acids, benzene, amino acids, organic acids, carbohydrates and fatty acyls. We systematically compared metabolome patterns of exosomes via machine learning from patients with recrudescence and patients without recrudescence and demonstrated a marker set consisting of 3'-UMP, palmitoleic acid, palmitaldehyde, and isobutyl decanoate for predicting ESCC recurrence with an AUC of 98%. These metabolome signatures of exosomes retained a high absolute fold change value at all ESCC stages and were very likely associated with cancer metabolism, which could be potentially applied as novel biomarkers for diagnosis and prognosis of ESCC.
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Affiliation(s)
- Qingfu Zhu
- Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Liu Huang
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qinsi Yang
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, China
| | - Zheng Ao
- Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN 47405, USA.
| | - Rui Yang
- Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Jonathan Krzesniak
- Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN 47405, USA.
| | - Doudou Lou
- Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Liang Hu
- Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Xiaodan Dai
- Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Feng Guo
- Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN 47405, USA.
| | - Fei Liu
- Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, China
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16
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Zhao Z, Yang S, Zhou A, Li X, Fang R, Zhang S, Zhao G, Li P. Small Extracellular Vesicles in the Development, Diagnosis, and Possible Therapeutic Application of Esophageal Squamous Cell Carcinoma. Front Oncol 2021; 11:732702. [PMID: 34527593 PMCID: PMC8435888 DOI: 10.3389/fonc.2021.732702] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 08/09/2021] [Indexed: 12/14/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) persists among the most lethal and broad-spreading malignancies in China. The exosome is a kind of extracellular vesicle (EV) from about 30 to 200 nm in diameter, contributing to the transfer of specific functional molecules, such as metabolites, proteins, lipids, and nucleic acids. The paramount role of exosomes in the formation and development of ESCC, which relies on promoting intercellular communication in the tumor microenvironment (TME), is manifested with immense amounts. Tumor-derived exosomes (TDEs) participate in most hallmarks of ESCC, including tumorigenesis, invasion, angiogenesis, immunologic escape, metastasis, radioresistance, and chemoresistance. Published reports have delineated that exosome-encapsulated cargos like miRNAs may have utility in the diagnosis, as prognostic biomarkers, and in the treatment of ESCC. This review summarizes the function of exosomes in the neoplasia, progression, and metastasis of ESCC, which improves our understanding of the etiology and pathogenesis of ESCC, and presents a promising target for early diagnostics in ESCC. However, recent studies of exosomes in the treatment of ESCC are sparse. Thus, we introduce the advances in exosome-based methods and indicate the possible applications for ESCC therapy in the future.
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Affiliation(s)
- Zheng Zhao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Shuyue Yang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Anni Zhou
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiao Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Rui Fang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Guiping Zhao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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Jing Z, Chen K, Gong L. The Significance of Exosomes in Pathogenesis, Diagnosis, and Treatment of Esophageal Cancer. Int J Nanomedicine 2021; 16:6115-6127. [PMID: 34511909 PMCID: PMC8423492 DOI: 10.2147/ijn.s321555] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 08/16/2021] [Indexed: 12/21/2022] Open
Abstract
Esophageal cancer is one of the most common malignancy in China with high mortality. Understanding pathogenesis and identifying early diagnosis biomarkers can significantly improve the prognosis of patients with esophageal cancer. Exosomes are small vesicular structures containing a variety of components (including DNA, RNA, and proteins) mediating cell-to-cell material exchange and signal communication. Growing evidences have shown that exosomes and its components are involved in growth, metastasis and angiogenesis in cancer, and could also be used as diagnostic and prognostic markers. In this review, we summarized recent progress to elucidate the significance of exosomes in the esophageal cancer progression, microenvironment remodeling, therapeutic resistance, and immunosuppression. We also discuss the utility of exosomes as diagnostic and prognostic biomarkers and therapeutic tool in esophageal cancer.
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Affiliation(s)
- Zhao Jing
- Department of Oncology, Zhejiang Hospital, Hangzhou, Zhejiang, People's Republic of China
| | - Kai Chen
- Department of Cardiovascular and Thoracic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Ling Gong
- Department of Infectious Disease (Liver Diseases), The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, People's Republic of China
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Heydari R, Abdollahpour-Alitappeh M, Shekari F, Meyfour A. Emerging Role of Extracellular Vesicles in Biomarking the Gastrointestinal Diseases. Expert Rev Mol Diagn 2021; 21:939-962. [PMID: 34308738 DOI: 10.1080/14737159.2021.1954909] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Extracellular vesicles (EVs) play an important role in cell-cell communication and regulation of various cellular functions under physiological and pathophysiological conditions through transferring their cargo to recipient cells. Molecular constituents of EVs are a fingerprinting profile of secreting cells which can be used as promising prognostic, diagnostic, and drug-response biomarkers in clinical settings. AREAS COVERED The present study provides a brief introduction about the biology of EVs and reviews methodologies used for EV isolation and characterization as well as high-throughput strategies to analyze EV contents. Furthermore, this review highlights the importance and unique role of EVs in the development and progression of gastrointestinal (GI) diseases, especially GI cancers, and then discusses their potential use, particularly those isolated from body fluids, in diagnosis and prognosis of GI diseases. EXPERT OPINION In-depth analysis of EV content can lead to the identification of new potential biomarkers for early diagnosis and prognosis prediction of GI diseases. The use of a more targeted approach by establishing more reproducible and standardized methods to decrease variations and obtain desired EV population as well as revisiting large pools of identified biomarkers and their evaluation in larger patient cohorts can result in the introduction of more reliable biomarkers in clinic.
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Affiliation(s)
- Raheleh Heydari
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Faezeh Shekari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Advanced Therapy Medicinal Product Technology Development Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Anna Meyfour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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19
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Extracellular Vesicles as a Novel Liquid Biopsy-Based Diagnosis for the Central Nervous System, Head and Neck, Lung, and Gastrointestinal Cancers: Current and Future Perspectives. Cancers (Basel) 2021; 13:cancers13112792. [PMID: 34205183 PMCID: PMC8200014 DOI: 10.3390/cancers13112792] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/28/2021] [Accepted: 06/02/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary To improve clinical outcomes, early diagnosis is mandatory in cancer patients. Several diagnostic approaches have been proposed, however, the main drawback relies on the invasive procedures required. Extracellular vesicles (EVs) are bilayer lipid membrane structures released by almost all cells and transferred to remote sites via the bloodstream. The observation that their cargo reflects the cell of origin has opened a new frontier for non-invasive biomarker discovery in oncology. Moreover, since EVs can be recovered from different body fluids, their impact as a Correctdiagnostic tool has gained particular interest. Hence, in the last decade, several studies using different biological fluids have been performed, showing the valuable contributions of EVs as tumour biomarkers, and their improved diagnostic power when combined with currently available tumour markers. In this review, the most relevant data on the diagnostic relevance of EVs, alone or in combination with the well-established tumour markers, are discussed. Abstract Early diagnosis, along with innovative treatment options, are crucial to increase the overall survival of cancer patients. In the last decade, extracellular vesicles (EVs) have gained great interest in biomarker discovery. EVs are bilayer lipid membrane limited structures, released by almost all cell types, including cancer cells. The EV cargo, which consists of RNAs, proteins, DNA, and lipids, directly mirrors the cells of origin. EVs can be recovered from several body fluids, including blood, cerebral spinal fluid (CSF), saliva, and Broncho-Alveolar Lavage Fluid (BALF), by non-invasive or minimally invasive approaches, and are therefore proposed as feasible cancer diagnostic tools. In this review, methodologies for EV isolation and characterization and their impact as diagnostics for the central nervous system, head and neck, lung, and gastrointestinal cancers are outlined. For each of these tumours, recent data on the potential clinical applications of the EV’s unique cargo, alone or in combination with currently available tumour biomarkers, have been deeply discussed.
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20
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Zhang L, Lv Q, Zheng Y, Chen X, Kong D, Huang W, Liu P, Jiang H, Jiang Y. A rapid and accurate method for screening T-2 toxin in food and feed using competitive AlphaLISA. FEMS Microbiol Lett 2021; 368:6184045. [PMID: 33755724 DOI: 10.1093/femsle/fnab029] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 03/19/2021] [Indexed: 01/01/2023] Open
Abstract
T-2 is a common mycotoxin contaminating cereal crops. Chronic consumption of food contaminated with T-2 toxin can lead to death, so simple and accurate detection methods in food and feed are necessary. In this paper, we establish a highly sensitive and accurate method for detecting T-2 toxin using AlphaLISA. The system consists of acceptor beads labeled with T-2-bovine serum albumin (BSA), streptavidin-labeled donor beads and biotinylated T-2 antibodies. T-2 in the sample matrix competes with T-2-BSA for antibodies. Adding biotinylated antibodies to the test well followed by T-2 and T-2-BSA acceptor beads yielded a detection range of 0.03-500 ng/mL. The half-maximal inhibitory concentration was 2.28 ng/mL and the coefficient of variation was <10%. In addition, this method had no cross-reaction with other related mycotoxins. This optimized method for extracting T-2 from food and feed samples achieved a recovery rate of approximately 90% in T-2 concentrations as low as 1 ng/mL, better than the performance of a commercial ELISA kit. This competitive AlphaLISA method offers high sensitivity, good specificity, good repeatability and simple operation for detecting T-2 toxin in food and feed.
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Affiliation(s)
- Liwen Zhang
- Anhui Medical University, Hefei, Anhui 230032, China.,State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, China
| | - Qingyu Lv
- State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, China
| | - Yuling Zheng
- State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, China
| | - Xuan Chen
- State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, China
| | - Decong Kong
- State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, China
| | - Wenhua Huang
- State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, China
| | - Peng Liu
- State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, China
| | - Hua Jiang
- State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, China
| | - Yongqiang Jiang
- Anhui Medical University, Hefei, Anhui 230032, China.,State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, China
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21
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Calanzani N, Druce PE, Snudden C, Milley KM, Boscott R, Behiyat D, Saji S, Martinez-Gutierrez J, Oberoi J, Funston G, Messenger M, Emery J, Walter FM. Identifying Novel Biomarkers Ready for Evaluation in Low-Prevalence Populations for the Early Detection of Upper Gastrointestinal Cancers: A Systematic Review. Adv Ther 2021; 38:793-834. [PMID: 33306189 PMCID: PMC7889689 DOI: 10.1007/s12325-020-01571-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 11/11/2020] [Indexed: 02/07/2023]
Abstract
Introduction Detecting upper gastrointestinal (GI) cancers in primary care is challenging, as cancer symptoms are common, often non-specific, and most patients presenting with these symptoms will not have cancer. Substantial investment has been made to develop biomarkers for cancer detection, but few have reached routine clinical practice. We aimed to identify novel biomarkers for upper GI cancers which have been sufficiently validated to be ready for evaluation in low-prevalence populations. Methods We systematically searched MEDLINE, Embase, Emcare, and Web of Science for studies published in English from January 2000 to October 2019 (PROSPERO registration CRD42020165005). Reference lists of included studies were assessed. Studies had to report on second measures of diagnostic performance (beyond discovery phase) for biomarkers (single or in panels) used to detect pancreatic, oesophageal, gastric, and biliary tract cancers. We included all designs and excluded studies with less than 50 cases/controls. Data were extracted on types of biomarkers, populations and outcomes. Heterogeneity prevented pooling of outcomes. Results We identified 149 eligible studies, involving 22,264 cancer cases and 49,474 controls. A total of 431 biomarkers were identified (183 microRNAs and other RNAs, 79 autoantibodies and other immunological markers, 119 other proteins, 36 metabolic markers, 6 circulating tumour DNA and 8 other). Over half (n = 231) were reported in pancreatic cancer studies. Only 35 biomarkers had been investigated in at least two studies, with reported outcomes for that individual marker for the same tumour type. Apolipoproteins (apoAII-AT and apoAII-ATQ), and pepsinogens (PGI and PGII) were the most promising biomarkers for pancreatic and gastric cancer, respectively. Conclusion Most novel biomarkers for the early detection of upper GI cancers are still at an early stage of matureness. Further evidence is needed on biomarker performance in low-prevalence populations, in addition to implementation and health economic studies, before extensive adoption into clinical practice can be recommended. Electronic Supplementary Material The online version of this article (10.1007/s12325-020-01571-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Natalia Calanzani
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
| | - Paige E Druce
- Centre for Cancer Research and Department of General Practice, University of Melbourne, Victoria, Australia
| | - Claudia Snudden
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Kristi M Milley
- Centre for Cancer Research and Department of General Practice, University of Melbourne, Victoria, Australia
| | - Rachel Boscott
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Dawnya Behiyat
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Smiji Saji
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Javiera Martinez-Gutierrez
- Centre for Cancer Research and Department of General Practice, University of Melbourne, Victoria, Australia
- Department of Family Medicine, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Jasmeen Oberoi
- Centre for Cancer Research and Department of General Practice, University of Melbourne, Victoria, Australia
| | - Garth Funston
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Mike Messenger
- Leeds Centre for Personalised Medicine and Health, University of Leeds, Leeds, UK
| | - Jon Emery
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Centre for Cancer Research and Department of General Practice, University of Melbourne, Victoria, Australia
| | - Fiona M Walter
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Centre for Cancer Research and Department of General Practice, University of Melbourne, Victoria, Australia
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22
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Oncoprotein 18 is necessary for malignant cell proliferation in bladder cancer cells and serves as a G3-specific non-invasive diagnostic marker candidate in urinary RNA. PLoS One 2020; 15:e0229193. [PMID: 32614890 PMCID: PMC7332083 DOI: 10.1371/journal.pone.0229193] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 06/15/2020] [Indexed: 12/28/2022] Open
Abstract
Background Urine-based diagnostics indicated involvement of oncoprotein 18 (OP18) in bladder cancer. In cell culture models we investigated the role of OP18 for malignant cell growth. Methods We analyzed 113 urine samples and investigated two human BCa cell lines as a dual model: RT-4 and ECV-304, which represented differentiated (G1) and poorly differentiated (G3) BCa. We designed specific siRNA for down-regulation of OP18 in both cell lines. Phenotypes were characterized by cell viability, proliferation, and expression of apoptosis-related genes. Besides, sensitivity to cisplatin treatment was evaluated. Results Analysis of urine samples from patients with urothelial BCa revealed a significant correlation of the RNA-ratio OP18:uroplakin 1A with bladder cancer. High urinary ratios were mainly found in moderately to poorly differentiated tumors (grade G2-3) that were muscle invasive (stage T2-3), whereas samples from patients with more differentiated non-invasive BCa (G1) showed low OP18:UPK1A RNA ratios. Down-regulation of OP18 expression in ECV-304 shifted its phenotype towards G1 state. Further, OP18-directed siRNA induced apoptosis and increased chemo-sensitivity to cisplatin. Conclusions This study provides conclusive experimental evidence for the link between OP18-derived RNA as a diagnostic marker for molecular staging of BCa in non-invasive urine-based diagnostics and the patho-mechanistic role of OP18 suggesting this gene as a therapeutic target.
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23
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Gutkin DW, Shurin MR, El Azher MA, Shurin GV, Velikokhatnaya L, Prosser D, Shin N, Modugno F, Stemmer P, Elishaev E, Lokshin A. Novel protein and immune response markers of human serous tubal intraepithelial carcinoma of the ovary. Cancer Biomark 2020; 26:471-479. [PMID: 31658047 DOI: 10.3233/cbm-190528] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Ovarian cancer is the leading cause of death among gynecologic diseases in the USA and Europe. High-grade serous carcinoma (HGSC) of the ovary, the most aggressive type of ovarian cancer, is typically diagnosed at advanced stages when the 5-year survival is dismal. Since the cure rate for stage I HGSC is high, early detection of localized initial disease may improve patient outcomes. Serous tubal intraepithelial carcinoma (STIC) is considered to be a precursor lesion of HGSC. Discovery of biomarkers associated with STIC could aid in the development of an HGSC screening algorithm. Using immunohistochemical staining, we have demonstrated overexpression of UCHL1, ADAMTS13, and GAPDH in patients' STIC lesions, but not in cancer-free fallopian tubes. We additionally demonstrated a marked increase of T cells in perineoplastic stroma surrounding STIC lesions (largely CD4 + cells), but not in normal fallopian tubes and HGSC. FOXP3 + T regulatory cells are absent in STIC lesions but are present in HGSC. These observations indicate the microenvironment surrounding a STIC lesion may be immune promoting in contrast to the immune suppressive microenvironment of invasive carcinoma. In summary, we have identified UCHL1, ADAMTS13, and GAPDH as novel potentially useful markers associated with early stages of HGSC tumorigenesis and possibly contribute to STIC immunogenicity. The lack of immune suppression in the STIC microenvironment indicates that the immune system can still recognize and keep STIC controlled at this stage of the tumor development.
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Affiliation(s)
- Dmitriy W Gutkin
- Departments of Pathology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Michael R Shurin
- Departments of Pathology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.,Departments of Immunology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Mounia Alaoui El Azher
- Departments of Medicine, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Galina V Shurin
- Departments of Immunology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Liudmila Velikokhatnaya
- Departments of Medicine, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Denise Prosser
- Departments of Medicine, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Namhee Shin
- Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, USA
| | - Francesmary Modugno
- Departments of Obstetrics and Gynecology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Paul Stemmer
- Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, USA
| | - Esther Elishaev
- Departments of Obstetrics and Gynecology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Anna Lokshin
- Departments of Pathology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.,Departments of Medicine, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.,Departments of Obstetrics and Gynecology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
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24
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Huang Y, Deng X, Liang J. Review of the Application of Nanovesicles and the Human Interstitial Fluid in Gastrointestinal Premalignant Lesion Detection, Diagnosis, Prognosis and Therapy. Int J Nanomedicine 2019; 14:9469-9482. [PMID: 31819444 PMCID: PMC6896916 DOI: 10.2147/ijn.s208559] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 11/08/2019] [Indexed: 12/12/2022] Open
Abstract
Premalignant lesions arise from cells that abnormally proliferate and have a tendency to become cancerous. Developing methods to specifically target and remove these premalignant lesions is imperative to the prevention of malignant progression into gastrointestinal (GI) tumors. However, accurate detection and diagnosis of GI precancerous lesions is challenging, as these lesions show little or no structural change. Thus, this prevents early intervention and reduces the success rate of therapy. In this review, we performed a systematic analysis of the technological advancements in the combined application of nanovesicles (NVs) and the human interstitial fluid (HIF) to specifically target GI premalignant lesions. NVs, which include quantum dots (QDs), are small membranous vehicles of a nanometer diameter that are widely used as drug delivery vectors, therapeutic effectors and diagnostic sensors. HIF is the fluid that is present in human interstitial tissues (HITs) in which signaling molecules and agents travel and can be found throughout the body. HIF is exploited by tumor cells for their invasion, migration and spread. Because the HITs span the entire submucosa of the gastrointestinal tract, they have been increasingly targeted in GI tumor therapy. The challenges involved in the combined application of NVs and HIF in the detection, diagnosis, prognosis and therapy of GI premalignant lesions are also discussed.
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Affiliation(s)
- Yu Huang
- Liuzhou Traditional Chinese Medical Hospital, Liuzhou 545001, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xin Deng
- Guangxi University of Chinese Medicine, Nanning 530001, Guangxi Zhuang Autonomous Region, People's Republic of China.,Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China
| | - Jian Liang
- Guangxi University, Nanning 530004, Guangxi Zhuang Autonomous Region, People's Republic of China
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25
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Wang W, Fu S, Lin X, Zheng J, Pu J, Gu Y, Deng W, Liu Y, He Z, Liang W, Wang C. miR-92b-3p Functions As A Key Gene In Esophageal Squamous Cell Cancer As Determined By Co-Expression Analysis. Onco Targets Ther 2019; 12:8339-8353. [PMID: 31686859 PMCID: PMC6799829 DOI: 10.2147/ott.s220823] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 08/30/2019] [Indexed: 12/13/2022] Open
Abstract
Background Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy. The aims of the present study were to screen the critical miRNA and corresponding target genes that related to development of ESCC by weighted gene correlation network analysis (WGCNA) and investigate the functions by experimental validation. Methods Datasets of mRNA and miRNA expression data were downloaded from GEO. The R software was used for data preprocessing and differential expression gene analysis. The differentially expressed protein-coding genes (DEGs) and miRNAs (DEMs) were selected (FDR <0.05 or |Fold Change (FC)| >1.5). Meanwhile, 81 expression data of ESCC patients in TCGA combined with clinic information were applied by WGCNA to create networks. The correlational analyses between each module and clinical parameters were conducted, and enrichment analyses of GO and KEGG were subsequently performed. Then, a series of experiments were conducted in ESCC cells by use of miRNA mimics. Results In total, 4,023 DEGs and 328 DEMs were screened. After checking good genes and samples, 3,841 genes (3,696 DEGs and 145 DEMs) were used for WGCNA. As a consequence, altogether 11 gene modules were found. Among them, the brown modules were found to be strongly inversely associated with pathological grade. Meanwhile, has-mir-92b, the only miRNA in brown module, had a positive correlation with grade and negatively correlated with potential target gene (KFL4 and DCS2) in the same module. Furthermore, an increased expression of miR-92b-3p and down-regulated KLF4 and DSC2 protein was detected in the ESCC clinical samples. Up-regulated miR-92b-3p shortened G0/G1 phase and promote ESCC cells invasion and migration. Furthermore, we verified that DSC2 and KFL4 was target genes of miR-92b-3p by luciferase report assay. Conclusion WGCNA is an efficient approach to system biology. By this procedure, miR-92b-3p was identified as an ESCC-promoting gene by target KLF4 and DCS2.
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Affiliation(s)
- Wanpeng Wang
- Department of Radiotherapy, Lianshui County People's Hospital, Kangda College of Nanjing Medical University, Huai'an City, JiangSu, People's Republic of China
| | - Sengwang Fu
- Department of Gastroenterology and Hepatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Xiaolu Lin
- Department of Digestive Endoscopy, Fujian Provincial Hospital, Provincial Clinic Medical College, Fujian Medical University, Fuzhou, People's Republic of China
| | - Jinhui Zheng
- Department of Digestive Endoscopy, Fujian Provincial Hospital, Provincial Clinic Medical College, Fujian Medical University, Fuzhou, People's Republic of China
| | - Juan Pu
- Department of Radiotherapy, Lianshui County People's Hospital, Kangda College of Nanjing Medical University, Huai'an City, JiangSu, People's Republic of China
| | - Yun Gu
- Department of Thoracic Surgery, Lianshui County People's Hospital, Kangda College of Nanjing Medical University, Huai'an City, JiangSu, People's Republic of China
| | - Weijun Deng
- Department of Thoracic Surgery, Lianshui County People's Hospital, Kangda College of Nanjing Medical University, Huai'an City, JiangSu, People's Republic of China
| | - Yanyan Liu
- Department of Radiotherapy, Lianshui County People's Hospital, Kangda College of Nanjing Medical University, Huai'an City, JiangSu, People's Republic of China
| | - Zhongxiang He
- Department of Radiotherapy, Lianshui County People's Hospital, Kangda College of Nanjing Medical University, Huai'an City, JiangSu, People's Republic of China
| | - Wei Liang
- Department of Digestive Endoscopy, Fujian Provincial Hospital, Provincial Clinic Medical College, Fujian Medical University, Fuzhou, People's Republic of China
| | - Chengshi Wang
- Department of Radiotherapy, Lianshui County People's Hospital, Kangda College of Nanjing Medical University, Huai'an City, JiangSu, People's Republic of China
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26
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Etiology, cancer stem cells and potential diagnostic biomarkers for esophageal cancer. Cancer Lett 2019; 458:21-28. [PMID: 31125642 DOI: 10.1016/j.canlet.2019.05.018] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 04/10/2019] [Accepted: 05/15/2019] [Indexed: 12/19/2022]
Abstract
Esophageal cancer (EC) has been a leading cause of cancer death worldwide in part due to late detection and lack of precision treatment. EC includes two major malignancies, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Recent studies reveal that ESCC and EAC have distinct cell of origin and contain cancer stem cells (also known as tumor initiating cells) expressing different cell surface markers. These biomarkers have potentially important values for both early detection and finding effective therapy. In this review we summarize the updated findings for cell of origin and provide an overview of cancer cell biomarkers that have been tested for ESCC and EAC. In addition, we also discuss recent progress in the study of molecular mechanisms leading to these malignancies.
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27
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Su LL, Chang XJ, Zhou HD, Hou LB, Xue XY. Exosomes in esophageal cancer: A review on tumorigenesis, diagnosis and therapeutic potential. World J Clin Cases 2019; 7:908-916. [PMID: 31119136 PMCID: PMC6509264 DOI: 10.12998/wjcc.v7.i8.908] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 02/28/2019] [Accepted: 03/09/2019] [Indexed: 02/05/2023] Open
Abstract
Exosomes are nanovesicles secreted from various types of cells and can be isolated from various bodily fluids, such as blood and urine. The number and molecular contents, including proteins and RNA of exosomes, have been shown to reflect their parental cell origins, characteristics and biological behaviors. An increasing number of studies have demonstrated that exosomes play a role in the course of tumorigenesis, diagnosis, treatment and prognosis, although its precise functions in tumors are still unclear. Moreover, owing to a lack of a standard approach, exosomes and its contents have not yet been put into clinical practice successfully. This review aims to summarize the current knowledge on exosomes and its contents in esophageal cancer as well as the current limitations/challenges in its clinical application, which may provide a basis for an all-around understanding of the implementation of exosomes and exosomal contents in the surveillance and therapy of esophageal cancer.
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Affiliation(s)
- Lin-Lin Su
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Xiao-Jing Chang
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Huan-Di Zhou
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
- Department of Central Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Liu-Bing Hou
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
- Department of Central Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Xiao-Ying Xue
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
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28
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Wu H, Deng WW, Yang LL, Zhang WF, Sun ZJ. Expression and phosphorylation of Stathmin 1 indicate poor survival in head and neck squamous cell carcinoma and associate with immune suppression. Biomark Med 2018; 12:759-769. [PMID: 29847156 DOI: 10.2217/bmm-2017-0443] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
AIM Immunohistochemistry was used to detect the expression of Stathmin 1 and Serine 38 phospho-Stathmin 1 (p-Stathmin 1S38) in head and neck squamous cell carcinoma (HNSCC) and research its correlation with clinical parameters, survival and expression of immune checkpoint molecules. RESULTS Stathmin 1 and p-Stathmin 1S38 overexpression in primary HNSCC is associated with poor overall survival. Stathmin 1 expression is related to tumor size, category and lymph node status. Stathmin 1 expression correlates with PD-L1, TIM3, VISTA, B7-H3, B7-H4, LAG-3 and p-STAT3 expression in HNSCC. P-Stathmin 1S38 expression correlates with PD-L1, VISTA, B7-H4, LAG-3 and p-STAT3 in HNSCC. CONCLUSION We found expression of Stathmin 1 and p-Stathmin 1S38 indicates poor survival in HNSCC and may be associated with immune suppression.
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Affiliation(s)
- Hao Wu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, PR China
| | - Wei-Wei Deng
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, PR China
| | - Lei-Lei Yang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, PR China
| | - Wen-Feng Zhang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, PR China.,Department of Oral & Maxillofacial Head Neck Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, PR China
| | - Zhi-Jun Sun
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, PR China.,Department of Oral & Maxillofacial Head Neck Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, PR China
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