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Huang C, Liang C, Tong J, Zhong X, Luo L, Liang L, Wen Y, Zhong L, Deng J, Peng M, Wu W, Huang W, Xie A, Huang Y, Chen J. Soluble E-cadherin participates in BLM-induced pulmonary fibrosis by promoting EMT and lung fibroblast migration. ENVIRONMENTAL TOXICOLOGY 2024; 39:435-443. [PMID: 37792543 DOI: 10.1002/tox.23986] [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: 05/31/2023] [Revised: 09/03/2023] [Accepted: 09/18/2023] [Indexed: 10/06/2023]
Abstract
Soluble E-cadherin (sE-cad) is an 80 kDa fragment derived from E-cadherin that is shed from the cell surface through proteolytic cleavage and is a biomarker in various cancers that promotes invasion and migration. Alveolar epithelial destruction, aberrant lung fibroblast migration and inflammation contribute to pulmonary fibrosis. Here, we hypothesized that E-cadherin plays an important role in lung fibrosis. In this study, we found that E-cadherin was markedly increased in the bronchoalveolar lavage fluid (BALF) and serum of mice with pulmonary fibrosis and that blocking sE-cad with HECD-1, a neutralizing antibody targeting the ectodomain of E-cadherin, effectively inhibited myofibroblast accumulation and collagen deposition in the lungs after bleomycin (BLM) exposure. Moreover, transforming growth factor-β (TGF-β1) induced the shedding of sE-cad from A549 cells, and treatment with HECD-1 inhibited epithelial-mesenchymal transition (EMT) stimulated by TGF-β1. Fc-E-cadherin (Fc-Ecad), which is an exogenous form of sE-cad, robustly promoted lung fibroblast migration. E-cadherin participates in bleomycin (BLM)-induced lung fibrosis by promoting EMT in the alveolar epithelium and fibroblast activation. E-cadherin may be a novel therapeutic target for lung fibrosis.
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Affiliation(s)
- Chaowen Huang
- Department of Pulmonary and Critical Care Medicine, Jiangmen Institute of Respiratory Disease, Jiangmen Central Hospital, Jiangmen, China
| | - Congmin Liang
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Dongguan, Guangdong Province, China
| | - Jinzhai Tong
- Department of Pulmonary and Critical Care Medicine, Jiangmen Institute of Respiratory Disease, Jiangmen Central Hospital, Jiangmen, China
| | - Xueying Zhong
- Department of Pulmonary and Critical Care Medicine, Jiangmen Institute of Respiratory Disease, Jiangmen Central Hospital, Jiangmen, China
| | - Lishan Luo
- Department of Respiratory and Critical Care Medicine, Huizhou Municipal Central Hospital, Huizhou, Guangdong Province, China
| | - Liping Liang
- Department of Pulmonary and Critical Care Medicine, Jiangmen Institute of Respiratory Disease, Jiangmen Central Hospital, Jiangmen, China
| | - Yuting Wen
- Department of Pulmonary and Critical Care Medicine, Jiangmen Institute of Respiratory Disease, Jiangmen Central Hospital, Jiangmen, China
| | - Liandi Zhong
- Department of Pulmonary and Critical Care Medicine, Jiangmen Institute of Respiratory Disease, Jiangmen Central Hospital, Jiangmen, China
| | - Jiongrui Deng
- Department of Pulmonary and Critical Care Medicine, Jiangmen Institute of Respiratory Disease, Jiangmen Central Hospital, Jiangmen, China
| | - Ming Peng
- Department of Pulmonary and Critical Care Medicine, Jiangmen Institute of Respiratory Disease, Jiangmen Central Hospital, Jiangmen, China
| | - Weiliang Wu
- Department of Pulmonary and Critical Care Medicine, Jiangmen Institute of Respiratory Disease, Jiangmen Central Hospital, Jiangmen, China
| | - Weijian Huang
- Department of Pulmonary and Critical Care Medicine, Jiangmen Institute of Respiratory Disease, Jiangmen Central Hospital, Jiangmen, China
| | - Anlun Xie
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Dongguan, Guangdong Province, China
| | - Yanming Huang
- Department of Pulmonary and Critical Care Medicine, Jiangmen Institute of Respiratory Disease, Jiangmen Central Hospital, Jiangmen, China
| | - Jialong Chen
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Dongguan, Guangdong Province, China
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2
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Application of plasma membrane proteomics to identify cancer biomarkers. Proteomics 2023. [DOI: 10.1016/b978-0-323-95072-5.00008-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
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Serum and Pleural Soluble Cell Adhesion Molecules in Mesothelioma Patients: A Retrospective Cohort Study. Cancers (Basel) 2022; 14:cancers14122825. [PMID: 35740491 PMCID: PMC9221497 DOI: 10.3390/cancers14122825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/29/2022] [Accepted: 06/06/2022] [Indexed: 12/04/2022] Open
Abstract
Mesothelioma, a malignant neoplasm of mesothelial cells, has overall poor prognosis. Cell adhesion molecules (CAMs) are proteins that contribute to the immune response. In this study the clinical utility and prognostic significance of serum and pleural fluid soluble CAM (sCAM) levels were assessed in patients with mesothelioma. Mesothelioma patients were retrospectively recruited (2016-2020). Clinical characteristics, serum and pleural sCAM levels (sE-cadherin, sE-selectin, intercellular adhesion molecule 1 (sICAM-1) and vascular cell adhesion molecule 1 (sVCAM-1)) and histopathological characteristics were gathered. A total of 51 healthy controls were also recruited for a secondary cross-sectional analysis. 92 mesothelioma patients were analyzed (mean age 64.5 years, 87% males, performance status 0-2). Patients with increased pleural sE-cadherin had higher risk for disease progression (adjusted HR 1.11 (1.02, 1.20), p = 0.013). Serum and pleural sE-selectin were decreased in patients with high-grade mesothelioma. Patients with increased serum or pleural sE-selectin levels had lower risk for death (adjusted HR 0.88 (0.81, 0.96), p = 0.003; 0.90 (0.82, 0.99), p = 0.039, respectively). Serum sE-cadherin, sE-selectin and sICAM-1 levels were significantly increased in mesothelioma patients compared to healthy controls. Further studies are needed to indicate the clinical utility of serum and pleural sCAMs in mesothelioma patients.
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Singh R, Sharma A, Saji J, Umapathi A, Kumar S, Daima HK. Smart nanomaterials for cancer diagnosis and treatment. NANO CONVERGENCE 2022; 9:21. [PMID: 35569081 PMCID: PMC9108129 DOI: 10.1186/s40580-022-00313-x] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/26/2022] [Indexed: 05/14/2023]
Abstract
Innovations in nanomedicine has guided the improved outcomes for cancer diagnosis and therapy. However, frequent use of nanomaterials remains challenging due to specific limitations like non-targeted distribution causing low signal-to-noise ratio for diagnostics, complex fabrication, reduced-biocompatibility, decreased photostability, and systemic toxicity of nanomaterials within the body. Thus, better nanomaterial-systems with controlled physicochemical and biological properties, form the need of the hour. In this context, smart nanomaterials serve as promising solution, as they can be activated under specific exogenous or endogenous stimuli such as pH, temperature, enzymes, or a particular biological molecule. The properties of smart nanomaterials make them ideal candidates for various applications like biosensors, controlled drug release, and treatment of various diseases. Recently, smart nanomaterial-based cancer theranostic approaches have been developed, and they are displaying better selectivity and sensitivity with reduced side-effects in comparison to conventional methods. In cancer therapy, the smart nanomaterials-system only activates in response to tumor microenvironment (TME) and remains in deactivated state in normal cells, which further reduces the side-effects and systemic toxicities. Thus, the present review aims to describe the stimulus-based classification of smart nanomaterials, tumor microenvironment-responsive behaviour, and their up-to-date applications in cancer theranostics. Besides, present review addresses the development of various smart nanomaterials and their advantages for diagnosing and treating cancer. Here, we also discuss about the drug targeting and sustained drug release from nanocarriers, and different types of nanomaterials which have been engineered for this intent. Additionally, the present challenges and prospects of nanomaterials in effective cancer diagnosis and therapeutics have been discussed.
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Affiliation(s)
- Ragini Singh
- College of Agronomy, Liaocheng University, Liaocheng, 252059, Shandong, China.
| | - Ayush Sharma
- Amity Center for Nanobiotechnology and Nanomedicine (ACNN), Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, 303002, Rajasthan, India
| | - Joel Saji
- Amity Center for Nanobiotechnology and Nanomedicine (ACNN), Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, 303002, Rajasthan, India
| | - Akhela Umapathi
- Amity Center for Nanobiotechnology and Nanomedicine (ACNN), Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, 303002, Rajasthan, India
| | - Santosh Kumar
- Shandong Key Laboratory of Optical Communication Science and Technology, School of Physics Science and Information Technology, Liaocheng University, Liaocheng, 252059, Shandong, China
| | - Hemant Kumar Daima
- Amity Center for Nanobiotechnology and Nanomedicine (ACNN), Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, 303002, Rajasthan, India.
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Xie D, Chen Y, Wan X, Li J, Pei Q, Luo Y, Liu J, Ye T. The Potential Role of CDH1 as an Oncogene Combined With Related miRNAs and Their Diagnostic Value in Breast Cancer. Front Endocrinol (Lausanne) 2022; 13:916469. [PMID: 35784532 PMCID: PMC9243438 DOI: 10.3389/fendo.2022.916469] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 05/16/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Breast cancer (BC) is the leading cause of cancer-related mortality in females and the most common malignancy with high morbidity worldwide. It is imperative to develop new biomarkers and therapeutic targets for early diagnosis and effective treatment in BC. METHODS We revealed the oncogene function of cadherin 1 (CDH1) via bioinformatic analysis in BC. Moreover, miRNA database was utilized to predict miRNAs upstream of CDH1. Expression of CDH1-related miRNAs in BC and their values in BC stemness and prognosis were analyzed through TCGA-BRCA datasets. In addition, Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) were performed to explore the potential functions and signaling pathways of CDH1 in combination with CDH1-related miRNAs in BC progression. Finally, the differential expressions of soluble E-cadherin (sE-cad), which is formed by the secretion of CDH1-encoded E-cadherin into serum, analyzed by enzyme-linked immunosorbent assay (ELISA). Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) was used to detect the expression level of CDH1-related miRNAs in serum samples. RESULTS The mRNA and protein expressions of CDH1 were elevated in BC tissues compared with normal counterparts. Moreover, CDH1 overexpression was positively correlated with BC stage, metastatic, stemness characteristics, and poor prognosis among patients. In predictive analysis, miR-340, miR-185, and miR-20a target CDH1 and are highly expressed in BC. miR-20a overexpression alone was strongly associated with high stemness characteristics and poor prognosis of BC. Additionally, GO, KEGG, and hallmark effect gene set analysis demonstrated that CDH1 in combination with overexpression of miR-340, miR-185, or miR-20a participated in multiple biological processes and underly signaling pathways involving in tumorigenesis and development of BC. Finally, we provide experimental evidence that the combined determination of serum sE-cad and miR-20a in BC has highly diagnostic efficiency. CONCLUSIONS This study provides evidence for CDH1 as an oncogene in BC and suggests that miR-20a may regulate the stemness characteristics of BC to exert a pro-oncogenic effect by regulating CDH1. Moreover, sE-cad and miR-20a in serum can both be used as valid noninvasive markers for BC diagnosis.
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Sun J, Lu Z, Fu W, Lu K, Gu X, Xu F, Dai J, Yang Y, Jiang J. Exosome-Derived ADAM17 Promotes Liver Metastasis in Colorectal Cancer. Front Pharmacol 2021; 12:734351. [PMID: 34650435 PMCID: PMC8506248 DOI: 10.3389/fphar.2021.734351] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 09/08/2021] [Indexed: 12/21/2022] Open
Abstract
Exosomes derived from cancer cells are deemed important drivers of pre-metastatic niche formation at distant organs, but the underlying mechanisms of their effects remain largely unknow. Although the role of ADAM17 in cancer cells has been well studied, the secreted ADAM17 effects transported via exosomes are less understood. Herein, we show that the level of exosome-derived ADAM17 is elevated in the serum of patients with metastatic colorectal cancer as well as in metastatic colorectal cancer cells. Furthermore, exosomal ADAM17 was shown to promote the migratory ability of colorectal cancer cells by cleaving the E-cadherin junction. Moreover, exosomal ADAM17 overexpression as well as RNA interference results highlighted its function as a tumor metastasis-promoting factor in colorectal cancer in vitro and in vivo. Taken together, our current work suggests that exosomal ADAM17 is involved in pre-metastatic niche formation and may be utilized as a blood-based biomarker of colorectal cancer metastasis.
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Affiliation(s)
- Jinbing Sun
- Department of General Surgery, Changshu No. 1 People's Hospital, Affiliated Changshu Hospital of Soochow University, Changshu, China
| | - Zhihua Lu
- Department of Radiology, Changshu No. 1 People's Hospital, Affiliated Changshu Hospital of Soochow University, Changshu, China
| | - Wei Fu
- Department of Oncology, Changshu No. 1 People's Hospital, Affiliated Changshu Hospital of Soochow University, Changshu, China
| | - Kuangyi Lu
- Department of General Surgery, Changshu No. 1 People's Hospital, Affiliated Changshu Hospital of Soochow University, Changshu, China
| | - Xiuwen Gu
- Department of General Surgery, Changshu No. 1 People's Hospital, Affiliated Changshu Hospital of Soochow University, Changshu, China
| | - Feng Xu
- Department of General Surgery, Changshu No. 1 People's Hospital, Affiliated Changshu Hospital of Soochow University, Changshu, China
| | - Jiamin Dai
- Department of General Surgery, Changshu No. 1 People's Hospital, Affiliated Changshu Hospital of Soochow University, Changshu, China
| | - Yang Yang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jianlong Jiang
- Department of General Surgery, Changshu No. 1 People's Hospital, Affiliated Changshu Hospital of Soochow University, Changshu, China
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Soca-Chafre G, Avila-Vásquez H, Rueda-Romero C, Huerta-García E, Márquez-Ramírez SG, Ramos-Godinez P, López-Marure R, Alfaro-Moreno E, Montiel-Dávalos A. Airborne particulate matter upregulates expression of early and late adhesion molecules and their receptors in a lung adenocarcinoma cell line. ENVIRONMENTAL RESEARCH 2021; 198:111242. [PMID: 33933488 DOI: 10.1016/j.envres.2021.111242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 04/15/2021] [Accepted: 04/25/2021] [Indexed: 06/12/2023]
Abstract
BACKGROUND Epidemiological evidence associates chronic exposure to particulate matter (PM) with respiratory damage and lung cancer. Inhaled PM may induce systemic effects including inflammation and metastasis. This study evaluated whether PM induces expression of adhesion molecules in lung cancer cells promoting interaction with monocytes. METHODS The expression of early and late adhesion molecules and their receptors was evaluated in A549 (human lung adenocarcinoma) cells using a wide range of concentrations of PM2.5 and PM10. Then we evaluated cellular adhesion between A549 cells and U937 (human monocytes) cells after PM exposure. RESULTS We found higher expression of both early and late adhesion molecules and their ligands in lung adenocarcinoma cells exposed to PM2.5 and PM10 particles present in the air pollution at Mexico City from 0.03 μg/cm2 with a statistically significant difference (p ≤ 0.05). PM10 had stronger effect than PM2.5. Both PM also stimulated cellular adhesion between tumor cells and monocytes. CONCLUSIONS This study reveals a comprehensive expression profile of adhesion molecules and their ligands upregulated by PM2.5 and PM10 in A549 cells. Additionally these particles induced cellular adhesion of lung cancer cells to monocytes. This highlights possible implications of PM in two cancer hallmarks i.e. inflammation and metastasis, underlying the high cancer mortality associated with air pollution.
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Affiliation(s)
- Giovanny Soca-Chafre
- Basic Research Division, National Cancer Institute (INCAN), San Fernando 22, Sección XVI, Tlalpan, 14080, Mexico City (CDMX), Mexico.
| | - Herminia Avila-Vásquez
- Basic Research Division, National Cancer Institute (INCAN), San Fernando 22, Sección XVI, Tlalpan, 14080, Mexico City (CDMX), Mexico.
| | - Cristhiam Rueda-Romero
- Basic Research Division, National Cancer Institute (INCAN), San Fernando 22, Sección XVI, Tlalpan, 14080, Mexico City (CDMX), Mexico.
| | - Elizabeth Huerta-García
- Multidisciplinary Academic Division of Jalpa de Méndez, Autonomous Juárez University of Tabasco, Mexico.
| | | | - Pilar Ramos-Godinez
- Electron Microscopy Laboratory, Department of Pathology, INCAN, CDMX, Mexico.
| | - Rebeca López-Marure
- Department of Physiology, National Institute of Cardiology "Ignacio Chávez", CDMX, Mexico.
| | | | - Angélica Montiel-Dávalos
- Basic Research Division, National Cancer Institute (INCAN), San Fernando 22, Sección XVI, Tlalpan, 14080, Mexico City (CDMX), Mexico.
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Lin JC, Wang CC, Jiang RS, Wang WY, Liu SA. Application of proximity ligation assays to identify potential plasma biomarkers in oral cavity cancer patients: A case control study. Cancer Biomark 2021; 29:17-23. [PMID: 32568177 DOI: 10.3233/cbm-191195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Practical cancer biomarkers for oral cavity cancer are currently in limited use. OBJECTIVE We aimed to investigate the differences in soluble E-cadherin between patients with oral cavity cancer and matched healthy participants via Proximity Ligation Assay (PLA). METHODS Samples were taken from both patients diagnosed with oral cavity cancer, as well as non-cancerous participants. PLA was used to detect soluble E-cadherin and Cycle threshold (Ct) values derived from qPCR in order to calculate the number of starting amplicons. RESULTS In total, 74 patients with oral cavity cancer and 55 matched non-cancerous participants were included for final analysis. The Ct value of E-cadherin was found to be lower in oral cavity cancer patients when compared with that of the matched non-cancerous participants (20.72 ± 0.39 versus 21.27 ± 0.45, P< 0.001). Using a Ct value of 20.9 as a cut-off point, the sensitivity and specificity of discriminating patients with oral cavity cancer from the healthy controls was 63.5% and 87.3%, respectively. CONCLUSION Plasma soluble E-cadherin levels were significantly higher in patients with oral cavity cancer when compared with those from the matched non-cancerous participants.
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Affiliation(s)
- Jin-Ching Lin
- Department of Radiation Oncology, Changhua Christian Hospital, Changhua, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Chen-Chi Wang
- Department of Otolaryngology, Taichung Veterans General Hospital, Taichung, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Rong-San Jiang
- Department of Otolaryngology, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Wen-Yi Wang
- Department of Nursing, HungKuang University, Taichung, Taiwan
| | - Shih-An Liu
- Department of Otolaryngology, Taichung Veterans General Hospital, Taichung, Taiwan.,Center for Quality Management, Taichung Veterans General Hospital, Taichung, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
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9
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Chen H, Tang X, Han TL, Zhu JN, Zhou W, Baker PN, Chen C, Zhang H. Potential role of FoxO3a in the regulation of trophoblast development and pregnancy complications. J Cell Mol Med 2021; 25:4363-4372. [PMID: 33811439 PMCID: PMC8093966 DOI: 10.1111/jcmm.16499] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 03/03/2021] [Accepted: 03/18/2021] [Indexed: 12/13/2022] Open
Abstract
The forkhead box O3a protein (FoxO3a) has been reported to regulate tumour invasion and migration, but little is known about the molecular mechanism or its role in trophoblast invasion and migration into the uterus. In this study, we aim to explore its role in trophoblast development and placenta‐related pregnancy complications and the potential mechanism. Levels of FoxO3a and its phosphorylated form (p‐FoxO3a) in placental tissue from healthy pregnant women and pre‐eclampsia patients were first compared. Then, HTR‐8/SVneo cells were transfected with lentiviral vectors to deplete and overexpress FoxO3a. Western blot, immunohistochemistry, Cell Counting Kit‐8, wound‐healing assay, Matrigel invasion assay, cell apoptosis, cell cycle assay, RNA sequencing, qRT‐PCR and ChIP‐qPCR were performed on the cells to study the potential role of FoxO3a and the underlying mechanism. We found the expression of FoxO3a was decreased, whereas p‐FoxO3a was increased in pre‐eclampsia placentae. FoxO3a depletion significantly reduced transcription of the promoter region of intercellular cell adhesion molecule‐1 (ICAM1) gene in ChIP assays and led to reduced invasion and migration of trophoblast cells, arrested cell cycle in G1 phase and increased apoptosis under oxidative stress. Our results suggested that FoxO3a may play a role in the regulation of trophoblast invasion and migration during placental development, which may be because of its affinity to the ICAM1 promotor.
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Affiliation(s)
- Hao Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China.,The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, Chongqing, China
| | - Xin Tang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China.,The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, Chongqing, China
| | - Ting-Li Han
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jia-Nan Zhu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China.,The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, Chongqing, China
| | - Wei Zhou
- Department of Obstetrics, Chongqing Health Center for Women and Children, Chongqing, China
| | - Philip N Baker
- Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China.,College of Medicine, Biological Sciences and Psychology, University of Leicester, Leicester, UK
| | - Chang Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China.,Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Hua Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China
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10
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CD82 Suppresses ADAM17-Dependent E-Cadherin Cleavage and Cell Migration in Prostate Cancer. DISEASE MARKERS 2020; 2020:8899924. [PMID: 33204367 PMCID: PMC7654213 DOI: 10.1155/2020/8899924] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 09/17/2020] [Accepted: 10/13/2020] [Indexed: 01/29/2023]
Abstract
CD82 acts as a tumor suppressor in a series of steps in malignant progression. Here, we identified a novel function of CD82 on posttranslational regulating E-cadherin in prostate cancer. In our study, the declined expression of CD82 was verified in prostate cancer tissues and cell lines compared with normal tissue and cell lines. Functionally, CD82 inhibited cell migration and E-cadherin cleavage from the cell membrane in prostate cancer cell. Further study proved that a disintegrin and metalloproteinase ADAM17 as an executor of E-cadherin cleavage mediated the inhibitory regulation of CD82 in E-cadherin shedding in prostate cancer. Specifically, CD82 interacted with ADAM17 and inhibited its metalloprotease activity, which led to the descent of E-cadherin shedding. These results show a nuanced but important role of CD82 in nontranscriptional regulation of E-cadherin, which may help to understand the intricate regulation of dysfunctional adhesion molecule in cancer progression.
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11
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Ahmed I, Sozmen M. Expression of PDGF-A, PDGFRA, integrin subunit alpha V and selectin E is increased in canine cutaneous fibrosarcomas. Biotech Histochem 2020; 96:546-554. [PMID: 33034211 DOI: 10.1080/10520295.2020.1832256] [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: 10/23/2022] Open
Abstract
We investigated the expression of platelet derived growth factor alpha (PDGFA); its receptor, PDGFRA; integrin subunit alpha V; and selectin E in cutaneous fibrosarcomas in dogs. Ten cases of canine fibrosarcomas were obtained from the archive of the Department of Pathology, Ondokuz Mayis University, Samsun. Tissue sections were cut and stained with hematoxylin and eosin, Alcian blue-periodic acid Schiff, Masson's trichrome, and also immunostained. Eight tumors classified as spontaneous fibrosarcomas exhibited interwoven bundles of spindle shaped cells with oval to plump nuclei and scant cytoplasm, while two tumors exhibited features of injection site fibrosarcoma with peripheral infiltration of mononuclear cells and intratumor necrosis. We found that neoplastic cells from all cases exhibited cytoplasmic expression of PDGFA, and cytoplasmic and nuclear staining for PDGFRA. Integrin subunit alpha V immunostaining was observed in all cases, while selectin E expression was observed in vascular endothelial cells and neoplastic cells. A significant positive correlation was found between the expression of PDGFA and integrin subunit alpha V. Our findings indicate that PDGFA, PDGFRA, integrin subunit alpha V and selectin E are expressed strongly in canine cutaneous fibrosarcomas and may contribute to tumor progression.
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Affiliation(s)
- Ishtiaq Ahmed
- Department of Pathology, University of Veterinary and Animal Sciences , Lahore, Pakistan
| | - Mahmut Sozmen
- Department of Pathology, Faculty of Veterinary Medicine, Ondokuz Mayis University , Samsun, Turkey
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12
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Wu M, Tong X, Wang D, Wang L, Fan H. Soluble intercellular cell adhesion molecule-1 in lung cancer: A meta-analysis. Pathol Res Pract 2020; 216:153029. [PMID: 32853940 DOI: 10.1016/j.prp.2020.153029] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 05/03/2020] [Accepted: 05/18/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Many recent studies have investigated the prognostic, diagnostic, and progressive features of soluble intercellular cell adhesion molecule-1 (sICAM-1) in lung cancer patients, but the results remained inconsistent. This study aimed to explore the value of serum sICAM-1 in patients with lung cancer. METHODS A comprehensive systematic literature search in the Wanfang databases, china national knowledge infrastructure, Pubmed, and Embase was carried out update to June 15, 2019. The standard mean difference (SMD), hazard ratio (HR), and 95% confidence interval (95% CI) were applied to investigate the effect sizes. RESULTS 23 observational studies were included. According to our results, the serum sICAM-1 concentrations in patients with lung cancer were significantly higher than that in controls (healthy controls: SMD: 4.08, 95% CI: 3.14-5.02, P < 0.001; benign lung diseases controls : SMD: 1.48, 95% CI: 0.23-2.73,P = 0.02). Fortunately, a subgroup analysis was performed by language, treatment status, and lung cancer types, and the statistical results were similar. Serum sICAM-1 levels were markedly higher in stage III/IV than stage I/II (SMD: 1.96, 95% CI: 1.08-2.84, P < 0.001), Additionally, lung cancer patients with lymph node metastasis had a higher concentrations of serum sICAM-1(SMD: 1.83, 95% CI: 0.95-2.72, P < 0.001), as well as with distant metastasis (SMD: 0.86, 95% CI: 0.47-1.25, P < 0.001). Additionally, patients with higher sICAM-1 levels were related to a significantly poorer prognosis (progression free survival: HR: 1.16, 95% CI: 1.07-1.26, P < 0.001; overall survival: HR: 1.45, 95% CI: 1.17-1.79, P = 0.001). CONCLUSIONS Our study suggested that serum sICAM-1 levels may act as a potential marker for diagnosing lung cancer and predicting its staging, and were negatively correlated with prognosis of lung cancer.
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Affiliation(s)
- Man Wu
- Department of Respiratory and Critical Care Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, 610041, China
| | - Xiang Tong
- Department of Respiratory and Critical Care Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, 610041, China
| | - Dongguang Wang
- Department of Respiratory and Critical Care Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, 610041, China
| | - Lei Wang
- Department of Respiratory and Critical Care Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, 610041, China
| | - Hong Fan
- Department of Respiratory and Critical Care Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, 610041, China.
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13
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Monitoring Immune Responses in Neuroblastoma Patients during Therapy. Cancers (Basel) 2020; 12:cancers12020519. [PMID: 32102342 PMCID: PMC7072382 DOI: 10.3390/cancers12020519] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 02/14/2020] [Accepted: 02/18/2020] [Indexed: 12/11/2022] Open
Abstract
Neuroblastoma (NBL) is the most common extracranial solid tumor in childhood. Despite intense treatment, children with this high-risk disease have a poor prognosis. Immunotherapy showed a significant improvement in event-free survival in high-risk NBL patients receiving chimeric anti-GD2 in combination with cytokines and isotretinoin after myeloablative consolidation therapy. However, response to immunotherapy varies widely, and often therapy is stopped due to severe toxicities. Objective markers that help to predict which patients will respond or develop toxicity to a certain treatment are lacking. Immunotherapy guided via immune monitoring protocols will help to identify responders as early as possible, to decipher the immune response at play, and to adjust or develop new treatment strategies. In this review, we summarize recent studies investigating frequency and phenotype of immune cells in NBL patients prior and during current treatment protocols and highlight how these findings are related to clinical outcome. In addition, we discuss potential targets to improve immunogenicity and strategies that may help to improve therapy efficacy. We conclude that immune monitoring during therapy of NBL patients is essential to identify predictive biomarkers to guide patients towards effective treatment, with limited toxicities and optimal quality of life.
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Gao R, Sang N. Quasi-ultrafine particles promote cell metastasis via HMGB1-mediated cancer cell adhesion. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2020; 256:113390. [PMID: 31706768 DOI: 10.1016/j.envpol.2019.113390] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 10/11/2019] [Accepted: 10/12/2019] [Indexed: 06/10/2023]
Abstract
With increasingly severe air pollution, the aggravated health risks of particulate matter, especially ultrafine particles, are emerging as an urgent and sensitive topic. Considering the heterogeneity and complexity of ultrafine particles, there is insufficient evidence about their toxic effects and possible molecular mechanisms. To address this question, we analyzed the emission characteristics of quasi-ultrafine particles collected during winter in a typical coal-burning city, Taiyuan, and confirmed their contribution to lung cancer cell adhesion and metastasis. For the specific mechanism, we revealed that the endocytosis of quasi-ultrafine particles stimulated the release of HMGB1, induced NFκB-facilitated proinflammatory cytokine production through the interaction of HMGB1 with RAGE, and resulted in cancer-endothelial cell adhesion. These findings remind us of the potential effects of anthropogenic quasi-ultrafine particle pollution and provide a theoretical reference for the mitigation of tumorigenesis in a severe particulate matter contaminated environment.
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Affiliation(s)
- Rui Gao
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi, 030006, People's Republic of China
| | - Nan Sang
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi, 030006, People's Republic of China.
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15
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Zhang L, Pu D, Liu D, Wang Y, Luo W, Tang H, Huang Y, Li W. Identification and validation of novel circulating biomarkers for early diagnosis of lung cancer. Lung Cancer 2019; 135:130-137. [DOI: 10.1016/j.lungcan.2019.06.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 06/01/2019] [Accepted: 06/17/2019] [Indexed: 10/26/2022]
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16
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Tsaur I, Hüsch T, Jüngel E, Schneider F, Schneider M, Haferkamp A, Thomas C, Lieb V, Wach S, Taubert H, Chun FKH, Blaheta RA. sE-cadherin is upregulated in serum of patients with renal cell carcinoma and promotes tumor cell dissemination in vitro. Urol Oncol 2019; 37:355.e1-355.e9. [PMID: 31005422 DOI: 10.1016/j.urolonc.2019.03.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Revised: 02/25/2019] [Accepted: 03/03/2019] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Cadherin family proteins are involved in the tumorigenesis of several malignancies. However, their significance in renal cell carcinoma (RCC) has not been extensively investigated. The current study investigates the potential of several cadherins to perform as biomarkers for tumor detection and exert functional RCC activity. METHODS Pre- and postoperative concentrations of sE-cadherin, cadherin-6, N-cadherin, cadherin-11, cadherin-17, and cadherin-5 were measured in serum of patients undergoing surgery for RCC and correlated to clinical and histopathological parameters. Control serum was obtained from healthy volunteers. A498 and Caki-1 cells were incubated with sE-cadherin and assessed for cell growth, adhesion, and chemotaxis. RESULTS sE-cadherin was significantly upregulated in RCC patients, as compared to controls, and discriminated them with striking accuracy (area under the curve value 0.83). Serum levels remained stable several days after surgery. Treating A498 and Caki-1 cancer cells with various concentrations of sE-cadherin attenuated cell growth and adhesion, while chemotaxis was augmented. CONCLUSIONS sE-cadherin is overexpressed in serum of RCC patients and provides a functional cellular switch from sessility to aggressive dissemination. While sE-cadherin is not tumor-specific and thus inappropriate for population-based screening, further studies are warranted to investigate its role in monitoring RCC and employing it as a therapeutic target.
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Affiliation(s)
- Igor Tsaur
- University Medical Center Mainz, Department of Urology and Pediatric Urology, Mainz, Germany; University Hospital Frankfurt, Department of Urology, Frankfurt, Germany
| | - Tanja Hüsch
- University Medical Center Mainz, Department of Urology and Pediatric Urology, Mainz, Germany; University Hospital Frankfurt, Department of Urology, Frankfurt, Germany.
| | - Eva Jüngel
- University Medical Center Mainz, Department of Urology and Pediatric Urology, Mainz, Germany
| | | | - Meike Schneider
- University Medical Center Mainz, Department of Urology and Pediatric Urology, Mainz, Germany
| | - Axel Haferkamp
- University Medical Center Mainz, Department of Urology and Pediatric Urology, Mainz, Germany
| | - Christian Thomas
- University Medical Center Mainz, Department of Urology and Pediatric Urology, Mainz, Germany
| | - Verena Lieb
- University Hospital Erlangen, Department of Urology and Pediatric Urology, Erlangen, Germany
| | - Sven Wach
- University Hospital Erlangen, Department of Urology and Pediatric Urology, Erlangen, Germany
| | - Helge Taubert
- University Hospital Erlangen, Department of Urology and Pediatric Urology, Erlangen, Germany
| | - Felix K-H Chun
- University Hospital Frankfurt, Department of Urology, Frankfurt, Germany
| | - Roman A Blaheta
- University Hospital Frankfurt, Department of Urology, Frankfurt, Germany
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17
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Suraj J, Kurpińska A, Zakrzewska A, Sternak M, Stojak M, Jasztal A, Walczak M, Chlopicki S. Early and late endothelial response in breast cancer metastasis in mice: simultaneous quantification of endothelial biomarkers using a mass spectrometry-based method. Dis Model Mech 2019; 12:dmm.036269. [PMID: 30683749 PMCID: PMC6451429 DOI: 10.1242/dmm.036269] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 01/17/2019] [Indexed: 12/11/2022] Open
Abstract
The endothelium plays an important role in cancer metastasis, but the mechanisms involved are still not clear. In the present work, we characterised the changes in endothelial function at early and late stages of breast cancer progression in an orthotopic model of murine mammary carcinoma (4T1 cells). Endothelial function was analysed based on simultaneous microflow liquid chromatography–tandem mass spectrometry using multiple reaction monitoring (microLC/MS-MRM) quantification of 12 endothelium-related biomarkers, including those reflecting glycocalyx disruption – syndecan-1 (SDC-1), endocan (ESM-1); endothelial inflammation – vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin (E-sel); endothelial permeability – fms-like tyrosine kinase 1 (FLT-1), angiopoietin 2 (Angpt-2); and haemostasis – von Willebrand factor (vWF), tissue plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), as well as those that are pathophysiologically linked to endothelial function – adrenomedullin (ADM) and adiponectin (ADN). The early phase of metastasis in mouse plasma was associated with glycocalyx disruption (increased SDC-1 and ESM-1), endothelial inflammation [increased soluble VCAM-1 (sVCAM-1)] and increased vascular permeability (Angpt-2). During the late phase of metastasis, additional alterations in haemostasis (increased PAI-1 and vWF), as well as a rise in ADM and substantial fall in ADN concentration, were observed. In conclusion, in a murine model of breast cancer metastasis, we identified glycocalyx disruption, endothelial inflammation and increased endothelial permeability as important events in early metastasis, while the late phase of metastasis was additionally characterised by alterations in haemostasis. Summary: A microLC/MS-MRM-based approach for simultaneous determination of endothelium-related biomarkers identified glycocalyx disruption, endothelial inflammation and increased endothelial permeability as important events in early pulmonary metastasis in a murine model of breast cancer metastasis.
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Affiliation(s)
- Joanna Suraj
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland.,Jagiellonian University Medical College, Faculty of Pharmacy, Chair and Department of Toxicology, Medyczna 9, 30-688 Krakow, Poland
| | - Anna Kurpińska
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Agnieszka Zakrzewska
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Magdalena Sternak
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Marta Stojak
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Agnieszka Jasztal
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Maria Walczak
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland .,Jagiellonian University Medical College, Faculty of Pharmacy, Chair and Department of Toxicology, Medyczna 9, 30-688 Krakow, Poland
| | - Stefan Chlopicki
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland .,Jagiellonian University Medical College, Faculty of Medicine, Chair of Pharmacology, Grzegorzecka 16, 31-531 Krakow, Poland
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18
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Abstract
Thrombosis is a major cause of morbidity and mortality in cancer patients. The pathogenesis of blood coagulation activation in oncological patients is complex and involves both clinical and biological factors. Abnormalities in one or more coagulation test are common in cancer patients, even without thrombotic manifestations, indicating an ongoing hypercoagulable condition. Moreover, venous thromboembolism (VTE) can be the first symptom of an occult malignancy in an otherwise healthy individual. The levels of laboratory markers of activation of blood coagulation parallel the development of malignancy, being the coagulant mechanisms important for both thrombogenesis and tumor progression. Besides general clinical risk factors for VTE, also disease-specific clinical factors, i.e., type and stage of the tumor, and anticancer therapies increase the thrombotic risk in these patients. Furthermore, biological factors, including the cancer cell-specific prothrombotic properties together with the host cell inflammatory response to the tumor, are relevant as well as unique players in the pathogenesis of the cancer-associated hypercoagulability. Cancer cells produce and release procoagulant and fibrinolytic proteins, inflammatory cytokines, and procoagulant microparticles. They also express adhesion molecules binding to the receptors of host vascular cells (i.e., endothelial cells, platelets, and leukocytes), thereby stimulating the prothrombotic properties of these normal cells, including the shed of cell-specific microparticles and neutrophil extracellular traps. Of interest, several genes responsible for the cellular neoplastic transformation drive the programs of hemostatic properties expressed by cancer tissues. A better understanding of such mechanisms will help the development of novel strategies to prevent and treat the Trousseau's syndrome (i.e., cancer-associated thrombosis).
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Affiliation(s)
- Anna Falanga
- Department of Transfusion Medicine and Hematology, Hospital Papa Giovanni XXIII, Bergamo, Italy.
- University of Milan Bicocca, School of Medicine and Surgery, Monza, Italy.
| | - Francesca Schieppati
- Department of Transfusion Medicine and Hematology, Hospital Papa Giovanni XXIII, Bergamo, Italy
| | - Laura Russo
- Department of Transfusion Medicine and Hematology, Hospital Papa Giovanni XXIII, Bergamo, Italy
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19
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Rutherford EJ, Hill ADK, Hopkins AM. Adhesion in Physiological, Benign and Malignant Proliferative States of the Endometrium: Microenvironment and the Clinical Big Picture. Cells 2018; 7:E43. [PMID: 29772648 PMCID: PMC5981267 DOI: 10.3390/cells7050043] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 05/09/2018] [Accepted: 05/11/2018] [Indexed: 12/13/2022] Open
Abstract
Although the developments in cellular and molecular biology over the last few decades have significantly advanced our understanding of the processes and players that regulate invasive disease, many areas of uncertainty remain. This review will discuss the contribution of dysregulated cell⁻cell and cell⁻matrix adhesion to the invasion in both benign and malignant contexts. Using the endometrium as an illustrative tissue that undergoes clinically significant invasion in both contexts, the adhesion considerations in the cells ("seed") and their microenvironment ("soil") will be discussed. We hope to orientate this discussion towards translational relevance for the diagnosis and treatment of endometrial conditions, which are currently associated with significant morbidity and mortality.
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Affiliation(s)
- Emily J Rutherford
- Department of Surgery, Royal College of Surgeons in Ireland, RCSI Smurfit Building, Beaumont Hospital, Dublin 9, Ireland.
| | - Arnold D K Hill
- Department of Surgery, Royal College of Surgeons in Ireland, RCSI Smurfit Building, Beaumont Hospital, Dublin 9, Ireland.
| | - Ann M Hopkins
- Department of Surgery, Royal College of Surgeons in Ireland, RCSI Smurfit Building, Beaumont Hospital, Dublin 9, Ireland.
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20
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Chen Z, Zhao L, Zhao F, Yang G, Wang JJ. Tetrandrine suppresses lung cancer growth and induces apoptosis, potentially via the VEGF/HIF-1α/ICAM-1 signaling pathway. Oncol Lett 2018; 15:7433-7437. [PMID: 29849794 DOI: 10.3892/ol.2018.8190] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Accepted: 06/21/2017] [Indexed: 01/23/2023] Open
Abstract
The present study investigated the effect of tetrandrine on lung cancer cell growth and apoptosis, and its possible underlying molecular mechanism. A549 human lung cancer cells were incubated with between 2.5 and 10 µM tetrandrine for 12, 24 and 48 h, following which the effect of tetrandrine on cell viability and apoptosis were assessed using an MTT assay and flow cytometry. ELISA and western blotting were used to analyze VEGF activity, and the expression of poly (ADP-ribose) polymerase (PARP), phosphorylated protein kinase B (Akt), Bcl-2-associated X protein (Bax), hypoxia inducible factor (HIF)-1α and inter-cellular adhesion molecule-1 (ICAM-1). Tetrandrine effectively suppressed the growth of and induced apoptosis in A549 lung cancer cells. The expression of PARP, Bax, intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial growth factor (VEGF) was significantly upregulated, and the phosphorylation of Akt and expression of HIF-1α was significantly suppressed in A549 lung cancer cells. Therefore, tetrandrine may suppress cell viability and induce apoptosis via the VEGF/HIF-1α/ICAM-1 signaling pathway.
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Affiliation(s)
- Zhuo Chen
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Liang Zhao
- Department of Thoracic Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, P.R. China
| | - Feng Zhao
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Guanghai Yang
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Jian Jun Wang
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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21
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Ma R, Xu H, Wu J, Sharma A, Bai S, Dun B, Jing C, Cao H, Wang Z, She JX, Feng J. Identification of serum proteins and multivariate models for diagnosis and therapeutic monitoring of lung cancer. Oncotarget 2017; 8:18901-18913. [PMID: 28121629 PMCID: PMC5386656 DOI: 10.18632/oncotarget.14782] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 12/27/2016] [Indexed: 12/14/2022] Open
Abstract
Lung cancer is one of the most prevalent cancers and has very poor treatment outcome. Biomarkers useful for screening and assessing early therapeutic response may significantly improve the therapeutic outcome but are still lacking. In this study, serum samples from 218 non-small cell lung cancer (NSCLC) patients, 34 small cell lung cancer (SCLC) patients and 171 matched healthy controls from China were analyzed for 11 proteins using the Luminex multiplex assay. Eight of the 11 proteins (OPN, SAA, CRP, CYFRA21.1, CEA, NSE, AGP and HGF) are significantly elevated in NSCLC and SCLC (p = 10−5−10−59). At the individual protein level, OPN has the best diagnostic value for NSCLC (AUC = 0.92), two acute phase proteins (SAA and CRP) have AUC near 0.83, while CEA and CYFRA21.1 also possess good AUC (0.81 and 0.77, respectively). More importantly, several three-protein combinations that contain OPN and CEA plus one of four proteins (CRP, SAA, CYFRA21.1 or NSE) have excellent diagnostic potential for NSCLC (AUC = 0.96). Four proteins (CYFRA21.1, CRP, SAA and NSE) are severely reduced and three proteins (OPN, MIF and NSE) are moderately decreased after platinum-based chemotherapy. Therapeutic response index (TRI) computed with 3–5 proteins suggests that approximately 25% of the NSCLC patients respond well to the therapy and TRI is significantly correlated with pre-treatment protein levels. Our data suggest that therapeutic response in NSCLC patients can be effectively measured but personalized biomarkers may be needed to monitor different subsets of patients.
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Affiliation(s)
- Rong Ma
- Clinical Cancer Research Center, Jiangsu Cancer Hospital, Nanjing Medical University Affiliated Cancer Hospital Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, 210009, China
| | - Heng Xu
- Jiangsu Province Institute of Materia Medica, Nanjing Tech University, Nanjing 211816, China
| | - Jianzhong Wu
- Clinical Cancer Research Center, Jiangsu Cancer Hospital, Nanjing Medical University Affiliated Cancer Hospital Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, 210009, China
| | - Ashok Sharma
- Center for Biotechnology and Genomic Medicine, and Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Shan Bai
- Center for Biotechnology and Genomic Medicine, and Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Boying Dun
- Center for Biotechnology and Genomic Medicine, and Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Changwen Jing
- Clinical Cancer Research Center, Jiangsu Cancer Hospital, Nanjing Medical University Affiliated Cancer Hospital Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, 210009, China
| | - Haixia Cao
- Clinical Cancer Research Center, Jiangsu Cancer Hospital, Nanjing Medical University Affiliated Cancer Hospital Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, 210009, China
| | - Zhuo Wang
- Clinical Cancer Research Center, Jiangsu Cancer Hospital, Nanjing Medical University Affiliated Cancer Hospital Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, 210009, China
| | - Jin-Xiong She
- Center for Biotechnology and Genomic Medicine, and Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Jifeng Feng
- Clinical Cancer Research Center, Jiangsu Cancer Hospital, Nanjing Medical University Affiliated Cancer Hospital Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, 210009, China
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Townsend MH, Anderson MD, Weagel EG, Velazquez EJ, Weber KS, Robison RA, O'Neill KL. Non-small-cell lung cancer cell lines A549 and NCI-H460 express hypoxanthine guanine phosphoribosyltransferase on the plasma membrane. Onco Targets Ther 2017; 10:1921-1932. [PMID: 28408844 PMCID: PMC5384690 DOI: 10.2147/ott.s128416] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
In both males and females, lung cancer is one of the most lethal cancers worldwide and accounts for >30% of cancer-related deaths. Despite advances in biomarker analysis and tumor characterization, there remains a need to find suitable biomarker antigen targets for treatment in late-stage lung cancer. Previous research on the salvage pathway enzyme TK1 shows a unique relationship with cancer patients as serum levels are raised according to cancer grade. To expand this analysis, the other salvage pathway enzymes were evaluated for possible upregulation within lung cancer. Adenine phosphoribosyltransferase, deoxycytidine kinase, and hypoxanthine guanine phosphoribosyltransferase (HPRT) were assessed for their presentation on two non-small-cell lung cancer cell lines NCI-H460 and A549. In the present study, we show that deoxycytidine kinase and adenine phosphoribosyltransferase have no significant relationship with the membrane of NCI-H460 cells. However, we found significant localization of HPRT to the membrane of NCI-H460 and A549 cells. When treated with anti-HPRT antibodies, the average fluorescence of the cell population increased by 24.3% and 12.9% in NCI-H460 and A549 cells, respectively, in comparison with controls. To ensure that expression was not attributed to cytoplasmic HPRT, confocal microscopy was performed to visualize HPRT binding on the plasma membrane. After staining NCI-H460 cells treated with both fluorescent antibodies and a membrane-specific dye, we observed direct overlap between HPRT and the membrane of the cancer cells. Additionally, gold-conjugated antibodies were used to label and quantify the amount of HPRT on the cell surface using scanning electron microscopy and energy-dispersive analysis X-ray. Further confirming HPRT presence, the gold weight percentage of the sample increased significantly when NCI-H460 cells were exposed to HPRT antibody (P=0.012) in comparison with isotype controls. Our results show that HPRT is localized on the surface of these non-small-cell lung cancer cell lines.
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Affiliation(s)
- Michelle H Townsend
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, USA
| | - Michael D Anderson
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, USA
| | - Evita G Weagel
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, USA
| | - Edwin J Velazquez
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, USA
| | - K Scott Weber
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, USA
| | - Richard A Robison
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, USA
| | - Kim L O'Neill
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, USA
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23
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Wang B, Liu J, Xiong Y, Yan Y, Sun B, Zhao Q, Duan L, Li P, Huang Y, Chen W. Soluble E-cadherin as a serum biomarker in patients with HBV-related liver diseases. Clin Biochem 2016; 49:1232-1237. [DOI: 10.1016/j.clinbiochem.2016.07.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 07/03/2016] [Accepted: 07/17/2016] [Indexed: 12/13/2022]
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Roggiani F, Mezzanzanica D, Rea K, Tomassetti A. Guidance of Signaling Activations by Cadherins and Integrins in Epithelial Ovarian Cancer Cells. Int J Mol Sci 2016; 17:ijms17091387. [PMID: 27563880 PMCID: PMC5037667 DOI: 10.3390/ijms17091387] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 08/11/2016] [Accepted: 08/13/2016] [Indexed: 12/12/2022] Open
Abstract
Epithelial ovarian cancer (EOC) is the deadliest tumor among gynecological cancer in the industrialized countries. The EOC incidence and mortality have remained unchanged over the last 30 years, despite the progress in diagnosis and treatment. In order to develop novel and more effective therapeutic approaches, the molecular mechanisms involved in EOC progression have been thoroughly investigated in the last few decades. At the late stage, peritoneal metastases originate from the attachment of small clusters of cancer cells that shed from the primary site and carried by the ascites adhere to the abdominal peritoneum or omentum. This behavior suggests that cell–cell or cell–matrix adhesion mechanisms regulate EOC growth and dissemination. Complex downstream signalings, which might be influenced by functional cross-talk between adhesion molecules and co-expressed and activated signaling proteins, can affect the proliferation/survival and the migration/invasion of EOC cells. This review aimed to define the impact of the mechanisms of cell–cell, through cadherins, and cell–extracellular matrix adhesion, through integrins, on the signaling cascades induced by membrane receptors and cytoplasmic proteins known to have a role in the proliferation, migration and invasion of EOC cells. Finally, some novel approaches using peptidomimetic ligands to cadherin and integrins are summarized.
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Affiliation(s)
- Francesca Roggiani
- Unit of Molecular Therapies, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, Milan 20133, Italy.
| | - Delia Mezzanzanica
- Unit of Molecular Therapies, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, Milan 20133, Italy.
| | - Katia Rea
- Unit of Molecular Therapies, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, Milan 20133, Italy.
| | - Antonella Tomassetti
- Unit of Molecular Therapies, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, Milan 20133, Italy.
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Molina R, Marrades RM, Augé JM, Escudero JM, Viñolas N, Reguart N, Ramirez J, Filella X, Molins L, Agustí A. Assessment of a Combined Panel of Six Serum Tumor Markers for Lung Cancer. Am J Respir Crit Care Med 2016; 193:427-37. [DOI: 10.1164/rccm.201404-0603oc] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
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Serum activated leukocyte cell adhesion molecule and intercellular adhesion molecule-1 in patients with gastric cancer: Can they be used as biomarkers? Biomed Pharmacother 2016; 77:86-91. [PMID: 26796270 DOI: 10.1016/j.biopha.2015.12.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2015] [Revised: 11/26/2015] [Accepted: 12/11/2015] [Indexed: 12/19/2022] Open
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Wang Y, Kong H, Zeng X, Liu W, Wang Z, Yan X, Wang H, Xie W. Activation of NLRP3 inflammasome enhances the proliferation and migration of A549 lung cancer cells. Oncol Rep 2016; 35:2053-64. [PMID: 26782741 DOI: 10.3892/or.2016.4569] [Citation(s) in RCA: 142] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 11/24/2015] [Indexed: 11/05/2022] Open
Abstract
Lung cancer is the leading cause of cancer death, and it is widely accepted that chronic inflammation is an important risk for the development of lung cancer. Now, it is recognized that the nucleotide-binding and oligomerization domain (NOD) like receptors (NLRs)-containing inflammasomes are involved in cancer-related inflammation. This study was designed to investigate the effects of NLR family pyrin domain containing protein 3 (NLRP3) inflammasome on the proliferation and migration of lung adenocarcinoma cell line A549. Using 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, scratch assay, and Transwell migration assay, we showed that activation of the NLRP3 inflammasome by LPS+ATP enhanced the proliferation and migration of A549 cells. Western blot analysis showed that activation of phosphorylation of Akt, ERK1/2, CREB and the expression of Snail increased, while the expression of E-cadherin decreased after the activation of NLRP3 inflammasome. Moreover, these effects were inhibited by the following treatments: i) downregulating the expression of NLRP3 by short hairpin RNA (shRNA) interference, ii) inhibiting the activation of NLRP3 inflammasome with a caspase-1 inhibitor, iii) blocking the interleukin-1β (IL-1β) and IL-18 signal transduction with IL-1 receptor antagonist (IL-1Ra) and IL-18 binding protein (IL-18BP). Collectively, these results indicate that NLRP3 inflammasome plays a vital role in regulating the proliferation and migration of A549 cells and it might be a potential target for the treatment of lung cancer.
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Affiliation(s)
- Yanli Wang
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Hui Kong
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Xiaoning Zeng
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Wenrui Liu
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Zailiang Wang
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Xiaopei Yan
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Hong Wang
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Weiping Xie
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
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Kamekura R, Nava P, Feng M, Quiros M, Nishio H, Weber DA, Parkos CA, Nusrat A. Inflammation-induced desmoglein-2 ectodomain shedding compromises the mucosal barrier. Mol Biol Cell 2015. [PMID: 26224314 PMCID: PMC4569309 DOI: 10.1091/mbc.e15-03-0147] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Proinflammatory cytokines promote desmoglein-2 (Dsg2) ectodomain shedding in intestinal epithelial cells. Epithelial exposure to Dsg2 ectodomains compromises intercellular adhesion while also promoting proliferation. These findings identify mechanisms by which mucosal inflammation–induced cleavage of Dsg2 influences intestinal epithelial homeostasis. Desmosomal cadherins mediate intercellular adhesion and control epithelial homeostasis. Recent studies show that proteinases play an important role in the pathobiology of cancer by targeting epithelial intercellular junction proteins such as cadherins. Here we describe the proinflammatory cytokine-induced activation of matrix metalloproteinase 9 and a disintegrin and metalloproteinase domain–containing protein 10, which promote the shedding of desmosomal cadherin desmoglein-2 (Dsg2) ectodomains in intestinal epithelial cells. Epithelial exposure to Dsg2 ectodomains compromises intercellular adhesion by promoting the relocalization of endogenous Dsg2 and E-cadherin from the plasma membrane while also promoting proliferation by activation of human epidermal growth factor receptor 2/3 signaling. Cadherin ectodomains were detected in the inflamed intestinal mucosa of mice with colitis and patients with ulcerative colitis. Taken together, our findings reveal a novel response pathway in which inflammation-induced modification of columnar epithelial cell cadherins decreases intercellular adhesion while enhancing cellular proliferation, which may serve as a compensatory mechanism to promote repair.
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Affiliation(s)
- Ryuta Kamekura
- Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322 Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 0608556, Japan
| | - Porfirio Nava
- Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322 Department of Physiology, Biophysics, and Neuroscience, Center for Research and Advanced Studies, Mexico DF 07360, Mexico
| | - Mingli Feng
- Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322 Department of Pathology, University of Michigan, Ann Arbor, MI 48109
| | - Miguel Quiros
- Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322 Department of Pathology, University of Michigan, Ann Arbor, MI 48109
| | - Hikaru Nishio
- Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322
| | - Dominique A Weber
- Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322
| | - Charles A Parkos
- Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322 Department of Pathology, University of Michigan, Ann Arbor, MI 48109
| | - Asma Nusrat
- Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322 Department of Pathology, University of Michigan, Ann Arbor, MI 48109
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Gu X, Ma C, Yuan D, Song Y. Circulating soluble intercellular adhesion molecule-1 in lung cancer: a systematic review. Transl Lung Cancer Res 2015; 1:36-44. [PMID: 25806153 DOI: 10.3978/j.issn.2218-6751.08.01] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2011] [Accepted: 08/08/2011] [Indexed: 12/22/2022]
Abstract
Soluble intercellular adhesion molecule-1(sICAM-1) has been implicated in tumor progression and metastasis. However the expression of circulating sICAM-1 as well as its diagnostic and prognostic value in patients with lung cancer remains controversial. We performed an electronic database (including PubMed, Web of Science, and Medline) search with the terms "ICAM", "intercellular adhesion molecule" and "lung cancer", and summarized the results of eligible studies in order to review the expression of sICAM-1 as well as its clinical significance in lung cancer. According to our literature search, we conducted a final analysis of 1258 patients from 16 studies. And we revealed that the circulating concentration of sICAM-1 in lung cancer patients was significantly higher than that in healthy controls. Additionally, baseline sICAM-1 levels apparently were associated with ECOG performance status, gender, histology type and disease stages. Furthermore, there seems to be a significantly inverse association between sICAM-1 levels, prognosis and response rate in NSCLC patients. In conclusion, sICAM-1 appeared to be a potential diagnostic and prognostic biomarker in lung cancer patients. Additional prospective studies are required to confirm this issue.
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Affiliation(s)
- Xiaoling Gu
- Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Chunyan Ma
- Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Dongmei Yuan
- Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Yong Song
- Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
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Atrial natriuretic peptide prevents cancer metastasis through vascular endothelial cells. Proc Natl Acad Sci U S A 2015; 112:4086-91. [PMID: 25775533 PMCID: PMC4386325 DOI: 10.1073/pnas.1417273112] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Most patients suffering from cancer die of metastatic disease. Surgical removal of solid tumors is performed as an initial attempt to cure patients; however, surgery is often accompanied with trauma, which can promote early recurrence by provoking detachment of tumor cells into the blood stream or inducing systemic inflammation or both. We have previously reported that administration of atrial natriuretic peptide (ANP) during the perioperative period reduces inflammatory response and has a prophylactic effect on postoperative cardiopulmonary complications in lung cancer surgery. Here we demonstrate that cancer recurrence after curative surgery was significantly lower in ANP-treated patients than in control patients (surgery alone). ANP is known to bind specifically to NPR1 [also called guanylyl cyclase-A (GC-A) receptor]. In mouse models, we found that metastasis of GC-A-nonexpressing tumor cells (i.e., B16 mouse melanoma cells) to the lung was increased in vascular endothelium-specific GC-A knockout mice and decreased in vascular endothelium-specific GC-A transgenic mice compared with control mice. We examined the effect of ANP on tumor metastasis in mice treated with lipopolysaccharide, which mimics systemic inflammation induced by surgical stress. ANP inhibited the adhesion of cancer cells to pulmonary arterial and micro-vascular endothelial cells by suppressing the E-selectin expression that is promoted by inflammation. These results suggest that ANP prevents cancer metastasis by inhibiting the adhesion of tumor cells to inflamed endothelial cells.
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Liang Z, Sun XY, Xu LC, Fu RZ. Abnormal expression of serum soluble E-cadherin is correlated with clinicopathological features and prognosis of breast cancer. Med Sci Monit 2014; 20:2776-82. [PMID: 25553984 PMCID: PMC4280058 DOI: 10.12659/msm.892049] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Increased amounts of soluble E-cadherin (E-cad) have been found in the serum in various cancers, but the role of serum soluble E-cad in the prognosis of breast cancer patients has not been explored in Asian populations. MATERIAL/METHOD Blood samples from 111 consecutive patients diagnosed with breast cancer and 55 healthy controls were investigated.Serum soluble E-cad expression levels were measured by enzyme-linked immunosorbent assay(ELISA) with an immunoassay kit according to the manufacturer's directions. Kaplan-Meier analyses were used to evaluate the association between serum soluble E-cad expression level and survival. All statistical tests were 2-sided. RESULTS The serum levels of soluble E-cad in breast cancer patients were significantly higher than those of the control group (2218.9±319.6 ng/ml vs. 742.8±91.7 ng/ml, p<0.001). Serum levels of soluble E-cad correlated significantly with TNM stage (P=0.007), tumor grade (P=0.03), and lymph node metastasis (P<0.001). Kaplan-Meier analysis with the log-rank test indicated that high serum levels of soluble E-cad had a significant impact on overall survival (55.4% vs. 81.4%; P=0.032) and disease-free survival (36.8% vs. 67.8%; P=0.002) in breast cancer. Multivariate analysis revealed that serum levels of soluble E-cad were independently associated with overall survival and disease-free survival in breast cancer patients. CONCLUSIONS Serum soluble E-cad level is an independent prognostic factor in Asian breast cancer patients.
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Affiliation(s)
- Zhi Liang
- Shandong University, Jinan, China (mainland)
| | - Xue-Yan Sun
- Reproductive Medical Center, Yantaishan Hospital, Yantai, China (mainland)
| | - Li-Cheng Xu
- Department of Breast Surgery, Yantaishan Hospital, Yantai, China (mainland)
| | - Rong-Zhan Fu
- Department of Breast and Thyroid Surgery, Qianfoshan Hospital, Jinan, China (mainland)
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Increased levels of exhaled sICAM1, sVCAM1, and sE-selectin in patients with non-small cell lung cancer. Respir Med 2014; 108:1670-6. [DOI: 10.1016/j.rmed.2014.08.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Revised: 08/07/2014] [Accepted: 08/12/2014] [Indexed: 11/19/2022]
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Adekola H, Romero R, Chaemsaithong P, Korzeniewski SJ, Dong Z, Yeo L, Hassan SS, Chaiworapongsa T. Endocan, a putative endothelial cell marker, is elevated in preeclampsia, decreased in acute pyelonephritis, and unchanged in other obstetrical syndromes. J Matern Fetal Neonatal Med 2014; 28:1621-32. [PMID: 25211383 PMCID: PMC4412749 DOI: 10.3109/14767058.2014.964676] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Objective: Endocan, a dermatan sulphate proteoglycan produced by endothelial cells, is considered a biomarker for endothelial cell activation/dysfunction. Preeclampsia is characterized by systemic vascular inflammation, and endothelial cell activation/dysfunction. Therefore, the objectives of this study were to determine whether: (1) plasma endocan concentrations in preeclampsia differ from those in uncomplicated pregnancies; (2) changes in plasma endocan concentration relate to the severity of preeclampsia, and whether these changes are specific or observed in other obstetrical syndromes such as small-for-gestational age (SGA), fetal death (FD), preterm labor (PTL) or preterm prelabor rupture of membranes (PROM); (3) a correlation exists between plasma concentration of endocan and angiogenic (placental growth factor or PlGF)/anti-angiogenic factors (soluble vascular endothelial growth factor receptor or sVEGFR-1, and soluble endoglin or sEng) among pregnancies complicated by preeclampsia; and (4) plasma endocan concentrations in patients with preeclampsia and acute pyelonephritis (both conditions in which there is endothelial cell activation) differ. Method: This cross-sectional study included the following groups: (1) uncomplicated pregnancy (n = 130); (2) preeclampsia (n = 102); (3) pregnant women without preeclampsia who delivered an SGA neonate (n = 51); (4) FD (n = 49); (5) acute pyelonephritis (AP; n = 35); (6) spontaneous PTL (n = 75); and (7) preterm PROM (n = 64). Plasma endocan concentrations were determined in all groups, and PIGF, sEng and VEGFR-1 plasma concentrations were measured by ELISA in the preeclampsia group. Results: (1) Women with preeclampsia had a significantly higher median plasma endocan concentration than those with uncomplicated pregnancies (p = 0.004); (2) among women with preeclampsia, the median plasma endocan concentration did not differ significantly according to disease severity (p = 0.1), abnormal uterine artery Doppler velocimetry (p = 0.7) or whether diagnosis was made before or after 34 weeks gestational age (p = 0.3); (3) plasma endocan concentration in women with preeclampsia correlated positively with plasma anti-angiogenic factor concentrations [sVEGFR-1: Spearman rho 0.34, p = 0.001 and sEng: Spearman rho 0.30, p = 0.003]; (4) pregnancies complicated by acute pyelonephritis with bacteremia had a lower median plasma endocan concentration than pregnancies complicated by acute pyelonephritis without bacteremia (p = 0.004), as well as uncomplicated pregnancies (p = 0.001); and (5) there was no significant difference in the median plasma endocan concentration between uncomplicated pregnancies and those complicated by FD, delivery of an SGA neonate, PTL or preterm PROM (other members of the “great obstetrical syndromes”; each p > 0.05). Conclusion: Median maternal plasma endocan concentrations were higher preeclampsia and lower in acute pyelonephritis with bacteremia than in uncomplicated pregnancy. No significant difference was observed in the median plasma endocan concentration between other great obstetrical syndromes and uncomplicated pregnancies. The difference in the direction of change of endocan in preeclampsia and acute pyelonephritis with bacteremia may be consistent with the view that both disease entities differ in pathogenic mechanisms, despite their associations with systemic vascular inflammation and endothelial cell activation/dysfunction.
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Affiliation(s)
- Henry Adekola
- a Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH , Bethesda , MD (Detroit, MI) , USA
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Levels of soluble E-cadherin in breast, gastric, and colorectal cancers. BIOMED RESEARCH INTERNATIONAL 2014; 2014:408047. [PMID: 25535613 PMCID: PMC4182303 DOI: 10.1155/2014/408047] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Accepted: 08/18/2014] [Indexed: 02/07/2023]
Abstract
Soluble E-cadherin is a 80 kDa protein fragment coming from the proteolytic cleavage of the extracellular domain of the full length epithelial cadherin, a molecule involved in cell adhesion/polarity and tissue morphogenesis. In comparison with normal epithelia, cancer cells show a decreased cadherin-mediated intercellular adhesion, and sE-cad levels normally increase in body fluids (blood and urine). This review focuses on soluble E-cadherin in sera of patients affected by three solid cancers (breast, gastric, and colorectal cancers) and how its levels correlate or not with some cancer parameters (e.g., dimension, progression, and localisation). We will describe the main proteomics approaches adopted to measure sE-cad both in vivo and in vitro and the most important findings about its behaviour in cancer dynamics.
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Zhang J, Xu L, Yang Z, Lu H, Hu D, Li W, Zhang Z, Liu B, Ma S. MicroRNA-10b indicates a poor prognosis of non-small cell lung cancer and targets E-cadherin. Clin Transl Oncol 2014; 17:209-14. [DOI: 10.1007/s12094-014-1213-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Accepted: 08/05/2014] [Indexed: 01/04/2023]
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Nava P, Kamekura R, Nusrat A. Cleavage of transmembrane junction proteins and their role in regulating epithelial homeostasis. Tissue Barriers 2014; 1:e24783. [PMID: 24665393 PMCID: PMC3879235 DOI: 10.4161/tisb.24783] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Revised: 04/19/2013] [Accepted: 04/23/2013] [Indexed: 02/07/2023] Open
Abstract
Epithelial tissues form a selective barrier that separates the external environment from the internal tissue milieu. Single epithelial cells are densely packed and associate via distinct intercellular junctions. Intercellular junction proteins not only control barrier properties of the epithelium but also play an important role in regulating epithelial homeostasis that encompasses cell proliferation, migration, differentiation and regulated shedding. Recent studies have revealed that several proteases target epithelial junction proteins during physiological maturation as well as in pathologic states such as inflammation and cancer. This review discusses mechanisms and biological consequences of transmembrane junction protein cleavage. The influence of junction protein cleavage products on pathogenesis of inflammation and cancer is discussed.
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Affiliation(s)
- Porfirio Nava
- Epithelial Pathobiology and Mucosal Inflammation Research Unit; Department of Pathology and Laboratory Medicine; Emory University School of Medicine; Atlanta, GA USA ; Department of Physiology; Biophysics and Neurosciences; Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV); México DF, Mexico
| | - Ryuta Kamekura
- Epithelial Pathobiology and Mucosal Inflammation Research Unit; Department of Pathology and Laboratory Medicine; Emory University School of Medicine; Atlanta, GA USA
| | - Asma Nusrat
- Epithelial Pathobiology and Mucosal Inflammation Research Unit; Department of Pathology and Laboratory Medicine; Emory University School of Medicine; Atlanta, GA USA
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Zhang Y, Wu JZ, Yang YQ, Ma R, Zhang JY, Feng JF. Expression of growth‑regulated oncogene‑1, hepatocyte growth factor, platelet‑derived growth factor‑AA and soluble E‑selectin and their association with high‑risk human papillomavirus infection in squamous cell carcinoma of the uterine cervix. Mol Med Rep 2014; 10:1013-24. [PMID: 24889672 DOI: 10.3892/mmr.2014.2293] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 05/15/2014] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to evaluate the clinical significance and prognostic value of growth‑regulated oncogene‑1 (GRO‑1), hepatocyte growth factor (HGF), platelet‑derived growth factor‑AA (PDGF‑AA), soluble E‑selectin (sE‑selectin) and high‑risk human papillomavirus (HPV; types 16, 18/45, 31 and 33/52/58/67) infection in cervical squamous cell carcinoma (CSCC). A total of 426 cases were enrolled in the present study, of which 292 cases were patients with CSCC, 43 were patients with cervical intraepithelial neoplasia (CIN) and 91 were healthy controls. Luminex xMAP technology was used to detect the serum levels of GRO‑1, HGF, PDGF‑AA and sE‑selectin in all cases and two‑channel fluorescence quantitative polymerase chain reaction was used to determine HPV DNA in cervical scrapings from CSCC and CIN patients. The results demonstrated that the serum levels of GRO‑1, HGF and sE‑selectin were significantly higher in patients with CSCC compared with patients with CIN and the healthy controls (P<0.0001). Compared with the CIN patients, the HPV positive rate in the CSCC patients significantly increased (P=0.013). The four factors were correlated with certain clinicopathological variables of CSCC patients to a certain degree (P<0.05) and the levels of HGF were closely associated with HPV infection (P=0.039). The receiver operating characteristic curves demonstrated that HGF obtained the highest diagnostic value compared with the other three factors. Multivariate Cox regression analysis demonstrated that the serum levels of HGF (P<0.0001), FIGO stage (P<0.0001) and pelvic lymph node metastasis (P=0.001) were independent prognostic factors in patients with CSCC, while high‑risk HPV infection did not show any significance in this analysis. These results demonstrated that HGF may be a useful prognostic biomarker rather than high‑risk HPV types in patients with CSCC.
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Affiliation(s)
- Ye Zhang
- Department of Chemotherapy, The Affiliated Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Jian-Zhong Wu
- Research Center of Clinical Oncology, The Affiliated Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Yong-Qin Yang
- Department of Radiotherapy, The Affiliated Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Rong Ma
- Research Center of Clinical Oncology, The Affiliated Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Jun-Ying Zhang
- Department of Oncology, Xuzhou Medical College, Xuzhou, Jiangsu 221000, P.R. China
| | - Ji-Feng Feng
- Department of Chemotherapy, The Affiliated Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
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Bajenova O, Chaika N, Tolkunova E, Davydov-Sinitsyn A, Gapon S, Thomas P, O'Brien S. Carcinoembryonic antigen promotes colorectal cancer progression by targeting adherens junction complexes. Exp Cell Res 2014; 324:115-23. [PMID: 24726916 DOI: 10.1016/j.yexcr.2014.04.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Revised: 03/25/2014] [Accepted: 04/04/2014] [Indexed: 12/18/2022]
Abstract
Oncomarkers play important roles in the detection and management of human malignancies. Carcinoembryonic antigen (CEA, CEACAM5) and epithelial cadherin (E-cadherin) are considered as independent tumor markers in monitoring metastatic colorectal cancer. They are both expressed by cancer cells and can be detected in the blood serum. We investigated the effect of CEA production by MIP101 colorectal carcinoma cell lines on E-cadherin adherens junction (AJ) protein complexes. No direct interaction between E-cadherin and CEA was detected; however, the functional relationships between E-cadherin and its AJ partners: α-, β- and p120 catenins were impaired. We discovered a novel interaction between CEA and beta-catenin protein in the CEA producing cells. It is shown in the current study that CEA overexpression alters the splicing of p120 catenin and triggers the release of soluble E-cadherin. The influence of CEA production by colorectal cancer cells on the function of E-cadherin junction complexes may explain the link between the elevated levels of CEA and the increase in soluble E-cadherin during the progression of colorectal cancer.
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Affiliation(s)
- Olga Bajenova
- Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg 199034, Russia; Department of Genetics and Biotechnology, St. Petersburg State University, St. Petersburg 199034, Russia; Department of Surgery and Biomedical Sciences, Creighton University, Omaha, NE 68178, USA.
| | - Nina Chaika
- Department of Surgery and Biomedical Sciences, Creighton University, Omaha, NE 68178, USA
| | - Elena Tolkunova
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia
| | | | | | - Peter Thomas
- Department of Surgery and Biomedical Sciences, Creighton University, Omaha, NE 68178, USA
| | - Stephen O'Brien
- Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg 199034, Russia
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Yilmaz U, Zeybek U, Kahraman OT, Kafadar AM, Toptas B, Yamak N, Celik F, Yaylim I. Investigation of ICAM-1 and β3 integrin gene variations in patients with brain tumors. Asian Pac J Cancer Prev 2013; 14:5929-34. [PMID: 24289603 DOI: 10.7314/apjcp.2013.14.10.5929] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Primary brain tumors constitute a small percent of all malignant cancers, but their etiology remains poorly understood. β3 integrin (ITGB3) has been recognized to play influential roles in angiogenesis, tumor growth and metastasis. Intercellular adhesion molecule-1 (ICAM-1) is a surface glycoprotein important for tumor invasion and angiogenesis. The aim of this study was to investigate whether specific genetic polymorphisms of ICAM-1 and ITGB3 could be associated with brain cancer development and progression in a Turkish population. Our study is the first to our knowledge to investigate the relationship between brain tumor risk and ICAM-1 and β3 integrin gene polymorphisms. MATERIALS AND METHODS The study covered 92 patients with primary brain tumors and 92 age-matched healthy control subjects. Evaluation of β3 integrin (Leu33Pro (rs5918)) and ICAM-1 (R241G (rs1799969) and K469E (rs5498)) gene polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS According to results of our research, the A allele of the ICAM-1 R241G gene polymorphism appeared to be a risk factor for primary brain tumors (p<0.001). Similarly, the frequency of the A mutant allele of ICAM-1 R241G was statistically significant in patients with brain tumors classified as glioma (p<0.001). When allele and genotype distributions of ICAM- 1 K469E, ICAM-1 R241G and β3 integrin Leu33Pro gene polymorphisms were evaluated with age, sex, and smoking, there were no statistically significant differences. Haplotype analysis revealed that the frequencies of GAC (rs1799969-rs5498-rs5918) and GAT (rs1799969-rs5498-rs5918) haplotypes were significantly lower in patients as compared with controls (p=0.001; p=0.036 respectively). CONCLUSIONS This study provides the first evidence that ICAM-1 R241G SNP significantly contributes to the risk of primary brain tumors in a Turkish population. In addition, our results suggest that ICAM-1 R241G in combination ICAM-1 K469E may have protective effects against the development of brain cancer.
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Affiliation(s)
- Umit Yilmaz
- Department of Molecular Medicine, The Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey E-mail :
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Kotteas EA, Gkiozos I, Tsagkouli S, Bastas A, Ntanos I, Saif MW, Syrigos KN. Soluble ICAM-1 levels in small-cell lung cancer: prognostic value for survival and predictive significance for response during chemotherapy. Med Oncol 2013; 30:662. [PMID: 23884579 DOI: 10.1007/s12032-013-0662-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2013] [Accepted: 07/05/2013] [Indexed: 10/26/2022]
Abstract
Intercellular adhesion molecule-1 (ICAM-1) is an adhesion molecule, member of the immunoglobulin gene superfamily that seems to participate in the evolution of the metastatic process. We investigated the significance of baseline soluble ICAM-1 levels on the outcome of patients with small-cell lung cancer and whether soluble ICAM-1 is a predictive marker for objective response during and after chemotherapy in patients with small-cell lung cancer. Fifty patients with recently diagnosed small-cell lung cancer, as well as 27 healthy smokers, were enrolled. Blood samples were collected at the time of diagnosis, during and at the end of chemotherapy. Data were correlated with the characteristics of the patients and survival as well as with ICAM-1 predictive role for objective response. Statistical significant values of baseline soluble ICAM between patients and controls (p < 0.001) were observed. Multivariate analysis revealed an elevated risk of death of 9 % in the first year after diagnosis for every 10 units of increased soluble ICAM-1 at the baseline (p = 0.046). Performance status and disease stage were also independent prognostic factors. Patients with extensive disease who achieved an objective response during chemotherapy showed a significant decrease (25.8 %) in their soluble ICAM-1 levels compared with baseline levels (p = 0.001). Alongside performance status and disease stage, baseline soluble ICAM-1 could be evaluated as an additional prognostic factor in patients with small-cell lung cancer. Also, a possible role for soluble ICAM-1 may exist as a predictive marker for objective response during chemotherapy for patients with extensive disease (p = 0.001).
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Affiliation(s)
- Elias A Kotteas
- Oncology Unit GPP, Sotiria General Hospital, Athens School of Medicine, 152, Mesogeion Av., 115 27, Athens, Greece
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Shukla HD, Vaitiekunas P, Cotter RJ. Advances in membrane proteomics and cancer biomarker discovery: current status and future perspective. Proteomics 2012; 12:3085-104. [PMID: 22890602 DOI: 10.1002/pmic.201100519] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2011] [Revised: 07/05/2012] [Accepted: 07/27/2012] [Indexed: 02/06/2023]
Abstract
Membrane proteomic analysis has been proven to be a promising tool for identifying new and specific biomarkers that can be used for prognosis and monitoring of various cancers. Membrane proteins are of great interest particularly those with functional domains exposed to the extracellular environment. Integral membrane proteins represent about one-third of the proteins encoded by the human genome and assume a variety of key biological functions, such as cell-to-cell communication, receptor-mediated signal transduction, selective transport, and pharmacological actions. More than two-thirds of membrane proteins are drug targets, highlighting their immensely important pharmaceutical significance. Most plasma membrane proteins and proteins from other cellular membranes have several PTMs; for example, glycosylation, phosphorylation, and nitrosylation, and moreover, PTMs of proteins are known to play a key role in tumor biology. These modifications often cause change in stoichiometry and microheterogeneity in a protein molecule, which is apparent during electrophoretic separation. Furthermore, the analysis of glyco- and phosphoproteome of cell membrane presents a number of challenges mainly due to their low abundance, their large dynamic range, and the inherent hydrophobicity of membrane proteins. Under pathological conditions, PTMs, such as phosphorylation and glycosylation are frequently altered and have been recognized as a potential source for disease biomarkers. Thus, their accurate differential expression analysis, along with differential PTM analysis is of paramount importance. Here we summarize the current status of membrane-based biomarkers in various cancers, and future perspective of membrane biomarker research.
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Affiliation(s)
- Hem D Shukla
- Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
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Kaffenberger SD, Morgan TM, Stratton KL, Boachie AM, Barocas DA, Chang SS, Cookson MS, Herrell SD, Smith JA, Clark PE. ABO blood group is a predictor of survival in patients undergoing surgery for renal cell carcinoma. BJU Int 2012; 110:E641-6. [PMID: 22958439 DOI: 10.1111/j.1464-410x.2012.11366.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
UNLABELLED What's known on the subject? and What does the study add? Some evidence suggests that ABO blood type may be a risk factor for cancer incidence and prognosis. For example, a large study recently discovered an increased incidence of pancreatic cancer in patients with non-O blood type; however, it is not known whether blood group correlates with outcomes in patients with RCC. We found a significant and independent association between ABO blood group and overall survival in patients undergoing surgery for locoregional RCC. Specifically, we identified non-O blood type as a predictor of mortality. OBJECTIVE • To determine whether ABO blood group is associated with survival after nephrectomy or partial nephrectomy for renal cell carcinoma (RCC). PATIENTS AND METHODS • We conducted a retrospective cohort study of 900 patients who underwent surgery for locoregional RCC between 1997 and 2008 at a single institution. • Covariates included age, gender, race, American Society of Anesthesiology Physical Status, preoperative anaemia and hypoalbuminemia, tumour characteristics, lymph node status, procedure performed, transfusion status and ABO blood group. • Primary outcomes were overall (OS) and disease-specific survival (DSS). • Univariable survival analyses were performed using the Kaplan-Meier and log-rank methods. Multivariable analysis was performed using a Cox proportional hazards model. RESULTS • The 3-year OS estimate was 75% (95%CI 70-79%) for O blood group and 68% (95% CI 63-73%) for non-O blood group (P= 0.072). The 3-year DSS was 81% (95% CI 76-85%) for O blood group and 76% (95%CI 71-80%) for non-O blood group (P= 0.053). • In the multivariable analysis for OS, non-O blood type was significantly associated with decreased OS (HR 1.68, 95%CI 1.18-2.39; P= 0.004) but not DSS (HR 1.53, 95%CI 0.97-2.41; P= 0.065). CONCLUSION • These data suggest that ABO blood group is independently associated with OS in patients undergoing surgery for locoregional RCC. ABO blood group has not been previously recognized as a predictor of survival in RCC.
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Affiliation(s)
- Samuel D Kaffenberger
- Vanderbilt University Medical Center, Department of Urologic Surgery, Nashville, TN 37215, USA.
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Nolen BM, Langmead CJ, Choi S, Lomakin A, Marrangoni A, Bigbee WL, Weissfeld JL, Wilson DO, Dacic S, Siegfried JM, Lokshin AE. Serum biomarker profiles as diagnostic tools in lung cancer. Cancer Biomark 2012; 10:3-12. [PMID: 22297547 PMCID: PMC4556364 DOI: 10.3233/cbm-2012-0229] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Computed tomography (CT) scanning has emerged as an effective means of early detection for lung cancer. Despite marked improvement over earlier methodologies, the low level of specificity demonstrated by CT scanning has limited its clinical implementation as a screening tool. A minimally-invasive biomarker-based test that could further characterize CT-positive patients based on risk of malignancy would greatly enhance its clinical efficacy. METHODS We performed an analysis of 81 serum proteins in 92 patients diagnosed with lung cancer and 172 CT-screened control individuals. We utilize a series of bioinformatics algorithms including Metropolis-Monte Carlo, artificial neural networks, Naïve Bayes, and additive logistic regression to identify multimarker panels capable of discriminating cases from controls with high levels of sensitivity and specificity in distinct training and independent validation sets. RESULTS A three-biomarker panel comprised of MIF, prolactin, and thrombospondin identified using the Metropolis-Monte Carlo algorithm provided the best classification with a %Sensitivity/Specificity/Accuracy of 74/90/86 in the training set and 70/93/82 in the validation set. This panel was effective in the classification of control individuals demonstrating suspicious pulmonary nodules and stage I lung cancer patients. CONCLUSIONS The selected serum biomarker panel demonstrated a high diagnostic utility in the current study and performance characteristics which compare favorably with previous reports. Further advancements may lead to the development of a diagnostic tool useful as an adjunct to CT-scanning.
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Affiliation(s)
- Brian M Nolen
- University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213, USA
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The impact of E-cadherin expression on non-small cell lung cancer survival: a meta-analysis. Mol Biol Rep 2012; 39:9621-8. [DOI: 10.1007/s11033-012-1827-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2012] [Accepted: 06/10/2012] [Indexed: 12/16/2022]
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Bigbee WL, Gopalakrishnan V, Weissfeld JL, Wilson DO, Dacic S, Lokshin AE, Siegfried JM. A multiplexed serum biomarker immunoassay panel discriminates clinical lung cancer patients from high-risk individuals found to be cancer-free by CT screening. J Thorac Oncol 2012; 7:698-708. [PMID: 22425918 PMCID: PMC3308353 DOI: 10.1097/jto.0b013e31824ab6b0] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Clinical decision making in the setting of computed tomography (CT) screening could benefit from accessible biomarkers that help predict the level of lung cancer risk in high-risk individuals with indeterminate pulmonary nodules. METHODS To identify candidate serum biomarkers, we measured 70 cancer-related proteins by Luminex xMAP (Luminex Corporation) multiplexed immunoassays in a training set of sera from 56 patients with biopsy-proven primary non-small-cell lung cancer and 56 age-, sex-, and smoking-matched CT-screened controls. RESULTS We identified a panel of 10 serum biomarkers-prolactin, transthyretin, thrombospondin-1, E-selectin, C-C motif chemokine 5, macrophage migration inhibitory factor, plasminogen activator inhibitor, receptor tyrosine-protein kinase, erbb-2, cytokeratin fragment 21.1, and serum amyloid A-that distinguished lung cancer patients from controls with an estimated balanced accuracy (average of sensitivity and specificity) of 76.0 ± 3.8% from 20-fold internal cross-validation. We then iteratively evaluated this model in an independent test and verification case/control studies confirming the initial classification performance of the panel. The classification performance of the 10-biomarker panel was also analytically validated using enzyme-linked immunosorbent assays in a second independent case/control population, further validating the robustness of the panel. CONCLUSIONS The performance of this 10-biomarker panel-based model was 77.1% sensitivity/76.2% specificity in cross-validation in the expanded training set, 73.3% sensitivity/93.3% specificity (balanced accuracy 83.3%) in the blinded verification set with the best discriminative performance in stage I/II cases: 85% sensitivity (balanced accuracy 89.2%). Importantly, the rate of misclassification of CT-screened controls was not different in most control subgroups with or without airflow obstruction or emphysema or pulmonary nodules. These biomarkers have potential to aid in the early detection of lung cancer and more accurate interpretation of indeterminate pulmonary nodules detected by CT screening.
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Affiliation(s)
- William L Bigbee
- Mass Spectrometry Platform, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
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Lung cancer cell invasion and expression of intercellular adhesion molecule-1 (ICAM-1) are attenuated by secretory phospholipase A₂ inhibition. J Thorac Cardiovasc Surg 2012; 143:405-11. [PMID: 22248682 DOI: 10.1016/j.jtcvs.2011.10.026] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2011] [Revised: 09/28/2011] [Accepted: 10/20/2011] [Indexed: 01/23/2023]
Abstract
OBJECTIVE Invasive lung tumors are associated with intercellular adhesion molecule-1 (ICAM-1) expression. Secretory phospholipase A(2) (sPLA(2)) enzymes produce inflammatory mediators that stimulate ICAM-1 expression, and upregulation of PLA(2) activity can enhance metastasis. We hypothesize a link between sPLA(2) activity, ICAM-1 expression, and tumor cell invasion. We propose that inhibition of sPLA(2) modulates ICAM-1 expression in cancer cells and attenuates their invasiveness. METHODS Human lung adenocarcinoma cells (A549) were treated with an ICAM-1 blocking antibody and assayed for invasion. Lung cancer cells (A549 and H358) were then treated with an sPLA(2) inhibitor and evaluated by immunoblotting for ICAM-1 expression. Next cells (A549) treated with sPLA(2) inhibitor were assayed for invasion. Finally, sPLA(2) messenger RNA and protein expression were evaluated by quantitative reverse-transcriptase polymerase chain reaction and immunofluorescence microscopy, respectively. Statistical analysis was performed by the Student t test or analysis of variance, as appropriate. RESULTS Antibody blockade of ICAM-1 decreased lung cancer cell invasion. sPLA(2) inhibition significantly reduced ICAM-1 expression and invasion. sPLA(2) inhibition also significantly decreased sPLA(2) mRNA expression and immunofluorescent staining of sPLA(2). CONCLUSIONS sPLA(2) plays a significant role in mediating the inflammatory signals that induce ICAM-1 expression in lung cancer cells. Inhibition of the enzyme can significantly decrease ICAM-1 expression and subsequent cancer cell invasion. This lays the groundwork for further investigation into the cellular mechanisms of sPLA(2) and its role in lung cancer.
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Tian MM, Sun Y, Li ZW, Wu Y, Zhao AL, Li JY. Polymorphisms of ICAM-1 are associated with gastric cancer risk and prognosis. World J Gastroenterol 2012; 18:368-74. [PMID: 22294843 PMCID: PMC3261532 DOI: 10.3748/wjg.v18.i4.368] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2011] [Revised: 10/19/2011] [Accepted: 10/26/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the association between single nucleotide polymorphisms (SNPs) in intercellular adhesion molecule-1 (ICAM-1) and the risk, biological behavior and prognosis of gastric cancer (GC) in Chinese population.
METHODS: The study group consisted of 332 GC patients and 380 healthy controls. Genotyping was performed using polymerase chain reaction and the results were confirmed by sequencing. The association of ICAM-1 K469E polymorphisms and the risk of GC were studied, and the correlation of ICAM-1 K469E polymorphisms with the clinicopathological parameters and prognosis of the patients with complete clinical and follow-up data was analyzed.
RESULTS: Carriers of AA genotype had a significantly increased risk of GC compared with carriers of AG and GG genotypes [odds ratios: 1.36; 95% confidence interval (CI): 1.01-1.84; P = 0.041]. GC patients with AA genotype were more prone to distant metastasis than those carrying AG and GG genotypes (18.9% vs 7.0%, respectively; P = 0.002). In addition, patients at stage IV had significantly more carriers of AA genotype than those of AG and GG genotype (27.4% vs 16.9%, respectively; P = 0.046). Follow-up study showed that the overall cumulative survival rate was 23.7% in AA genotype group and 42.9% in AG and GG genotypes group. In univariate analysis, AA genotype was correlated with the overall cumulative survival (P = 0.034). But in multivariate analysis, ICAM-1 polymorphism was not an independent prognostic factor for the overall survival (relative risk, 1.145; 95% CI: 0.851-1.540; P = 0.370).
CONCLUSION: Polymorphisms of ICAM-1 K469E can be a useful biomarker for identifying individuals with higher risk of GC, predicting disease progression, and guiding individualized treatment.
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Zhao Y, Zhou YN, Ran JT, Zou SJ, Li Q, Chen ZF. Clinical significance of serum levels of soluble E-cadherin in patients with gastric carcinoma. Shijie Huaren Xiaohua Zazhi 2011; 19:2668-2672. [DOI: 10.11569/wcjd.v19.i25.2668] [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] [Indexed: 02/06/2023] Open
Abstract
AIM: To measure serum levels of soluble E-cadherin (sE-cadherin) in patients with gastric cancer and to evaluate the relationship of serum levels of sE-cadherin with tumor clinicopathological features and patient survival.
METHODS: Peripheral blood samples were collected from 127 gastric cancer patients and 31 healthy controls from March 2003 to September 2004. Serum levels of sE-cadherin were measured using double-antibody sandwich enzyme-linked immunosorbent assay. The clinical pathological data and survive data for all patients were recorded.
RESULTS: Serum levels of sE-cadherin were significantly higher in patients with gastric cancer than in healthy controls (43.83 μg/L ± 15.77 μg/L vs 17.17 μg/L ± 5.38 μg/L, P = 0.000, t = 8.34). Serum levels of sE-cadherin were closely associated with tumor differentiation, depth of invasion and lymph node metastasis (all P < 0.05). Patients with lower levels of serum sE-cadherin had significant survival advantage over those with higher levels of serum sE-cadherin (P < 0.001), and such survival advantage was independent of depth of invasion, lymph node metastasis and tumor differentiation.
CONCLUSION: sE-cadherin may serve as a potential biological marker for the diagnosis and prognosis of gastric cancer.
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Salgia R. Prognostic significance of angiogenesis and angiogenic growth factors in nonsmall cell lung cancer. Cancer 2011; 117:3889-99. [PMID: 21858799 PMCID: PMC3160199 DOI: 10.1002/cncr.25935] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2010] [Revised: 11/30/2010] [Accepted: 12/16/2010] [Indexed: 01/22/2023]
Abstract
Currently, nonsmall-cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States. Angiogenesis, the formation of new vasculature, is a complex and tightly regulated process that promotes metastasis and disease progression in lung cancer and other malignancies. Developmental antiangiogenic agents have shown activity in NSCLC, and bevacizumab, an antiangiogenic monoclonal antibody, is approved for the treatment of patients with advanced disease. However, predictive biomarkers are needed to guide the administration of antiangiogenic agents. It is possible that angiogenic molecules could accurately predict patient response to targeted antiangiogenic therapies, which would allow individualized and perhaps more effective treatment. Angiogenic signaling molecules may also have value as prognostic indicators, which may be useful for the management of NSCLC. Here the author provides an overview of angiogenic molecules currently being investigated as prognostic biomarkers in NSCLC and discusses their potential to guide treatment choices.
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Affiliation(s)
- Ravi Salgia
- Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois, USA.
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