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Khalili-Tanha G, Radisky ES, Radisky DC, Shoari A. Matrix metalloproteinase-driven epithelial-mesenchymal transition: implications in health and disease. J Transl Med 2025; 23:436. [PMID: 40217300 PMCID: PMC11992850 DOI: 10.1186/s12967-025-06447-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Accepted: 03/30/2025] [Indexed: 04/14/2025] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a process in which epithelial cells, defined by apical-basal polarity and tight intercellular junctions, acquire migratory and invasive properties characteristic of mesenchymal cells. Under normal conditions, EMT directs essential morphogenetic events in embryogenesis and supports tissue repair. When dysregulated, EMT contributes to pathological processes such as organ fibrosis, chronic inflammation, and cancer progression and metastasis. Matrix metalloproteinases (MMPs)-a family of zinc-dependent proteases that degrade structural components of the extracellular matrix-sit at the nexus of this transition by dismantling basement membranes, activating pro-EMT signaling pathways, and cleaving adhesion molecules. When normally regulated, MMPs promote balanced ECM turnover and support the cyclical remodeling necessary for proper development, wound healing, and tissue homeostasis. When abnormally regulated, MMPs drive excessive ECM turnover, thereby promoting EMT-related pathologies, including tumor progression and fibrotic disease. This review provides an integrated overview of the molecular mechanisms by which MMPs both initiate and sustain EMT under physiological and disease conditions. It discusses how MMPs can potentiate EMT through TGF-β and Wnt/β-catenin signaling, disrupt cell-cell junction proteins, and potentiate the action of hypoxia-inducible factors in the tumor microenvironment. It discusses how these pathologic processes remodel tissues during fibrosis, and fuel cancer cell invasion, metastasis, and resistance to therapy. Finally, the review explores emerging therapeutic strategies that selectively target MMPs and EMT, ranging from CRISPR/Cas-mediated interventions to engineered tissue inhibitors of metalloproteinases (TIMPs), and demonstrates how such approaches may suppress pathological EMT without compromising its indispensable roles in normal biology.
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Affiliation(s)
- Ghazaleh Khalili-Tanha
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Evette S Radisky
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
| | - Derek C Radisky
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
| | - Alireza Shoari
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
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Cheng K, Wan S, Yang JW, Chen SY, Wang HL, Xu CH, Qiao SH, Li XR, Li Y. Applications of Biosensors in Bladder Cancer. Crit Rev Anal Chem 2024:1-20. [PMID: 38978228 DOI: 10.1080/10408347.2024.2373923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
Bladder cancer (BC) is the tenth most common cancer globally, predominantly affecting men. Early detection and treatment are crucial due to high recurrence rates and poor prognosis for advanced stages. Traditional diagnostic methods like cystoscopy and imaging have limitations, leading to the exploration of noninvasive methods such as liquid biopsy. This review highlights the application of biosensors in BC, including electrochemical and optical sensors for detecting tumor markers like proteins, nucleic acids, and other biomolecules, noting their clinical relevance. Emerging therapeutic approaches, such as antibody-drug conjugates, targeted therapy, immunotherapy, and gene therapy, are also explored, the role of biosensors in detecting corresponding biomarkers to guide these treatments is examined. Finally, the review addresses the current challenges and future directions for biosensor applications in BC, highlighting the need for large-scale clinical trials and the integration of advanced technologies like deep learning to enhance diagnostic accuracy and treatment efficacy.
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Affiliation(s)
- Kun Cheng
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, P.R. China
- Gansu Province Clinical Research Center for Urology, Lanzhou, P.R. China
| | - Shun Wan
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, P.R. China
- Gansu Province Clinical Research Center for Urology, Lanzhou, P.R. China
| | - Jian-Wei Yang
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, P.R. China
- Gansu Province Clinical Research Center for Urology, Lanzhou, P.R. China
| | - Si-Yu Chen
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, P.R. China
- Gansu Province Clinical Research Center for Urology, Lanzhou, P.R. China
| | - Hai-Long Wang
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, P.R. China
- Gansu Province Clinical Research Center for Urology, Lanzhou, P.R. China
| | - Chang-Hong Xu
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, P.R. China
- Gansu Province Clinical Research Center for Urology, Lanzhou, P.R. China
| | - Si-Hang Qiao
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, P.R. China
- Gansu Province Clinical Research Center for Urology, Lanzhou, P.R. China
| | - Xiao-Ran Li
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, P.R. China
- Gansu Province Clinical Research Center for Urology, Lanzhou, P.R. China
| | - Yang Li
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, P.R. China
- Gansu Province Clinical Research Center for Urology, Lanzhou, P.R. China
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Chang YP, Huang GK, Chen YC, Huang KT, Chen YM, Lin CY, Huang CC, Lin MC, Wang CC. E-cadherin expression in the tumor microenvironment of advanced epidermal growth factor receptor-mutant lung adenocarcinoma and the association with prognosis. BMC Cancer 2023; 23:569. [PMID: 37340370 DOI: 10.1186/s12885-023-10980-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 05/19/2023] [Indexed: 06/22/2023] Open
Abstract
BACKGROUND The expression of programmed death-ligand 1 (PD-L1), tumor-infiltrating lymphocytes (TILs), E-cadherin, and vimentin in lung cancer tumor microenvironment is known to impact patient survival or response to therapy. The expression of these biomarkers may also differ between primary lung tumors and brain metastatic tumors. In this study, we investigated the interaction between these biomarkers in lung tumors with or without concomitant brain metastasis and the interaction with paired brain metastatic tumors. METHODS The study included 48 patients with stage IV epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma. Sixteen of the forty-eight patients were diagnosed with brain metastasis, while the remaining thirty-two were not. All sixteen patients with brain metastasis had brain tumors. The expression of PD-L1, TILs (CD8+ T lymphocytes and FOXP3+ regulatory T lymphocytes), E-cadherin, and vimentin were evaluated using immunohistochemical (IHC) staining. RESULTS Patients with brain metastasis exhibited a higher frequency of exon 19 deletion and uncommon EGFR mutations, a higher lung tumor vimentin score, worse progression-free survival (PFS), and overall survival (OS) than patients without brain metastasis. IHC staining showed no difference between paired lung and brain tumors. Patients with low PD-L1 expression had better PFS and OS. After multivariate analysis, higher body mass index, the presence of brain metastasis, bone metastasis, and uncommon EGFR mutations were correlated with worse PFS, while the presence of brain metastasis and high lung tumor E-cadherin score was associated with worse OS. CONCLUSIONS In patients with stage IV EGFR-mutant lung adenocarcinoma, high E-cadherin expression in the lung tumor might be associated with worse OS. Vimentin expression in the lung tumor was positively related to the risk of brain metastasis.
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Affiliation(s)
- Yu-Ping Chang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Gong-Kai Huang
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
- Department of Laboratory Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yung-Che Chen
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
- Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kuo-Tung Huang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yu-Mu Chen
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chiung-Yu Lin
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Cheng Huang
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
- Biobank and Tissue Bank, Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Meng-Chih Lin
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chin-Chou Wang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
- Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
- Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi, Taiwan.
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Urine E-cadherin: A Marker for Early Detection of Kidney Injury in Diabetic Patients. J Clin Med 2020; 9:jcm9030639. [PMID: 32121033 PMCID: PMC7141221 DOI: 10.3390/jcm9030639] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 02/11/2020] [Accepted: 02/24/2020] [Indexed: 12/17/2022] Open
Abstract
Diabetic nephropathy (DN) is the main reason for end-stage renal disease. Microalbuminuria as the non-invasive available diagnosis marker lacks specificity and gives high false positive rates. To identify and validate biomarkers for DN, we used in the present study urine samples from four patient groups: diabetes without nephropathy, diabetes with microalbuminuria, diabetes with macroalbuminuria and proteinuria without diabetes. For the longitudinal validation, we recruited 563 diabetic patients and collected 1363 urine samples with the clinical data during a follow-up of 6 years. Comparative urinary proteomics identified four proteins Apolipoprotein A-I (APOA1), Beta-2-microglobulin (B2M), E-cadherin (CDH1) and Lithostathine-1-alpha (REG1A), which differentiated with high statistical strength (p < 0.05) between DN patients and the other groups. Label-free mass spectrometric quantification of the candidates confirmed the discriminatory value of E-cadherin and Lithostathine-1-alpha (p < 0.05). Immunological validation highlighted E-cadherin as the only marker able to differentiate significantly between the different DN stages with an area under the curve (AUC) of 0.85 (95%-CI: [0.72, 0.97]). The analysis of the samples from the longitudinal study confirmed the prognostic value of E-cadherin, the critical increase in urinary E-cadherin level was measured 20 ± 12.5 months before the onset of microalbuminuria and correlated significantly (p < 0.05) with the glomerular filtration rate measured by estimated glomerular filtration rate (eGFR).
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Venhuizen JH, Jacobs FJ, Span PN, Zegers MM. P120 and E-cadherin: Double-edged swords in tumor metastasis. Semin Cancer Biol 2020; 60:107-120. [DOI: 10.1016/j.semcancer.2019.07.020] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 07/26/2019] [Indexed: 12/11/2022]
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Yang J, Xiong Y, Zhou L, Huang Y, Chen W, Wang B. Soluble E-cadherin is associated with oxidative stress in patients with chronic HBV infection. J Med Virol 2019; 92:34-44. [PMID: 31429942 DOI: 10.1002/jmv.25571] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 08/11/2019] [Indexed: 12/11/2022]
Abstract
Mounting evidence indicates that serum soluble E-cadherin (sE-cadherin) serves as an important player in various physiological and pathological processes. However, the crosstalk between serum sE-cadherin and oxidative stress in chronic hepatitis B (CHB) remains to be illustrated. The main purpose of this study is to explore the molecular mechanisms underlying the function of sE-cadherin in CHB virus infection. Levels of serum sE-cadherin, total antioxidant capacity (TAC), glutathione (GSH), superoxide dismutase (SOD), total oxidant activity (TOA), NADPH oxidase 2 (NOX2), and malondialdehyde (MDA), from 51 patients with hepatitis B envelope antigen (HBeAg)-negative CHB, 54 patients with HBeAg-positive CHB, and 109 healthy individuals were detected by enzyme-linked immunosorbent assay. In our study, patients with CHB showed significantly higher serum sE-cadherin levels than healthy individuals (P < .01). Furthermore, we also found that the serum sE-cadherin levels were significantly negatively correlated with TAC, antioxidant enzymes (GSH and SOD) in patients with CHB, and that serum sE-cadherin concentrations were significantly positively correlated with liver enzyme markers (alanine transaminase and aspartate aminotransferase) and oxidative markers (TOA, NOX2, and MDA) in patients with CHB. Therefore, serum sE-cadherin may act as a new candidate biomarker for reflecting inflammation and oxidative stress status in the development and progression of hepatitis B virus infection.
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Affiliation(s)
- Jun Yang
- Department of Laboratory Medicine, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yuan Xiong
- Department of Laboratory Medicine, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China
| | - Lijing Zhou
- Department of Laboratory Medicine, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yong Huang
- Department of Laboratory Medicine, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Weixian Chen
- Department of Laboratory Medicine, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Bo Wang
- Department of Laboratory Medicine, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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Fonseca ICCFE, da Luz FAC, Uehara IA, Silva MJB. Cell-adhesion molecules and their soluble forms: Promising predictors of "tumor progression" and relapse in leukemia. Tumour Biol 2018; 40:1010428318811525. [PMID: 30486756 DOI: 10.1177/1010428318811525] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Some surface markers are used to discriminate certain leukemic subpopulations that retain a greater oncogenic potential than others, and, for this reason, they were termed as leukemic stem cells, similar to the concept of cancer stem cells in carcinoma. Among these surface markers are proteins involved in cell-cell adhesion or cell-matrix adhesion, and they may play a role in the relapse of leukemia, similar to metastasis in carcinomas. The most important are epithelial cadherin, neural cadherin, epithelial cell-adhesion molecule, and CD44, which can be cleaved and released, and their soluble forms were found increased in serum levels of cancer patients, being implicated, in some cases, with progression, metastases, and relapse. In this review, we highlighted the role of these four adhesion molecules in carcinomas and hematological malignancies, mainly leukemia, and discuss if the serum levels of soluble forms can be correlated with the surface protein status on the leukemic cells. Accession of the soluble forms looks attractive, but their use as markers in cancer must be studied in association with other parameters, as there are significant changes in levels in other pathological conditions besides cancer. Studies correlating the levels of the forms with the status of the membrane-bound proteins in leukemic (stem) cells and correlating those parameters with relapse in leukemia may afford important knowledge and applicability of those serum markers in clinical practice. For instance, the expression of the membrane-bound forms of these adhesion proteins may have promising clinical use in leukemia and other hematological malignancies.
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Affiliation(s)
| | - Felipe Andrés Cordero da Luz
- 1 Laboratory of Tumor Biomarkers and Osteoimmunology, Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, Brazil
- 2 Nucleus of Cancer Prevention and Research, Cancer Hospital, Federal University of Uberlândia, Uberlândia, Brazil
| | - Isadora Akemi Uehara
- 1 Laboratory of Tumor Biomarkers and Osteoimmunology, Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, Brazil
| | - Marcelo José Barbosa Silva
- 1 Laboratory of Tumor Biomarkers and Osteoimmunology, Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, Brazil
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8
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Turan T, Torun M, Atalay F, Gönenç A. Assessment of Vitronectin, Soluble Epithelial-Cadherin and TGF-β1 as a Serum Biomarker with Predictive Value for Endometrial and Ovarian Cancers. Turk J Pharm Sci 2017; 14:141-147. [PMID: 32454605 DOI: 10.4274/tjps.81994] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 04/13/2017] [Indexed: 12/01/2022]
Abstract
Objectives Extracellular matrix components, including vitronectin (VN), soluble epithelial-cadherin (sE-cadherin) and transforming growth factor-beta 1 (TGF-β1), play a key role in the invasion and metastasis of cancer. The objective of the study was to determine the clinical significance of serum levels of these molecules in patients with endometrial and ovarian cancers. Materials and Methods Serum levels of VN, sE-cadherin and TGF-β1 in patients with endometrial (n=28) and ovarian cancers (n=40) and healthy controls (n=41) were measured by ELISA using commercial kits. Results A significant difference was found in VN, sE-cadherin and TGF-β1 levels between patients and healthy controls (p<0.01, p<0.01 and p<0.05, respectively). Serum VN and sE-cadherin levels were decreased significantly in both endometrial and ovarian cancer patients compared to controls (p<0.01, p<0.01, respectively). Conversely, TGF-β1 levels were increased significantly in patients with ovarian cancer as compared to controls (p<0.01). There was no significant difference between healthy controls and endometrial cancer patients. Conclusion In conclusion, our study reveals that serum VN, sE-cadherin and TGF-β1 levels can be candidate targets for providing new diagnostic procedures in endometrial and ovarian cancers.
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Affiliation(s)
- Taylan Turan
- Gazi University, Faculty Of Pharmacy, Department Of Biochemistry, Ankara, Turkey
| | - Meral Torun
- Gazi University, Faculty Of Pharmacy, Department Of Biochemistry, Ankara, Turkey
| | - Funda Atalay
- Ankara Oncology Training And Research Hospital, Clinic Of Obstetrics And Gynecology, Ankara, Turkey
| | - Aymelek Gönenç
- Gazi University, Faculty Of Pharmacy, Department Of Biochemistry, Ankara, Turkey
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Expression of Epithelial-Mesenchymal Transition-related Factors in Adherent Placenta. Int J Gynecol Pathol 2016; 34:584-9. [PMID: 26447356 DOI: 10.1097/pgp.0000000000000190] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Epithelial-mesenchymal transition is a key process influencing cancer progression and metastasis. The purpose of this study was to investigate the expression of epithelial-mesenchymal transition-related factors in chorionic villi and decidual cells in adherent placenta. The current study included 19 patients diagnosed with adherent placenta after hysterectomy. The expression of E-cadherin, Vimentin, Snail, and transforming growth factor-β in placental tissues was analyzed by immunohistochemical staining. Immunostaining intensity was semiquantitatively evaluated using the HSCORE algorithm. In the chorionic villi of the invasive part (placenta with invasion into myometrium), E-cadherin expression was significantly lower than that in the noninvasive part (placenta with no invasion). In the decidual cells of the invasive part, expression of transforming growth factor-β and Snail significantly increased. These results suggest that epithelial-mesenchymal transition may contribute to excessive trophoblast invasion into the myometrium in adherent placenta.
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10
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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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11
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Abstract
High Throughput Biological Data (HTBD) requires detailed analysis methods and from a life science perspective, these analysis results make most sense when interpreted within the context of biological pathways. Bayesian Networks (BNs) capture both linear and nonlinear interactions and handle stochastic events in a probabilistic framework accounting for noise making them viable candidates for HTBD analysis. We have recently proposed an approach, called Bayesian Pathway Analysis (BPA), for analyzing HTBD using BNs in which known biological pathways are modeled as BNs and pathways that best explain the given HTBD are found. BPA uses the fold change information to obtain an input matrix to score each pathway modeled as a BN. Scoring is achieved using the Bayesian-Dirichlet Equivalent method and significance is assessed by randomization via bootstrapping of the columns of the input matrix. In this study, we improve on the BPA system by optimizing the steps involved in "Data Preprocessing and Discretization", "Scoring", "Significance Assessment", and "Software and Web Application". We tested the improved system on synthetic data sets and achieved over 98% accuracy in identifying the active pathways. The overall approach was applied on real cancer microarray data sets in order to investigate the pathways that are commonly active in different cancer types. We compared our findings on the real data sets with a relevant approach called the Signaling Pathway Impact Analysis (SPIA).
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12
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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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13
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Grieve AG, Rabouille C. Extracellular cleavage of E-cadherin promotes epithelial cell extrusion. J Cell Sci 2014; 127:3331-46. [DOI: 10.1242/jcs.147926] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Epithelial cell extrusion and subsequent apoptosis is a key mechanism to prevent accumulation of excess cells. Conversely, when driven by oncogene expression, apical cell extrusion is followed by proliferation and represents an initial step of tumorigenesis. E-cadherin (E-cad), the main component of adherens junctions, has been shown to be essential for epithelial cell extrusion, but its mechanistic contribution remains unclear. Here, we provide clear evidence that cell extrusion can be driven by E-cad cleavage, both in a wild type and oncogenic environment. We first show that CDC42 activation in a single epithelial cell results in its efficient MMP-sensitive extrusion through MEK signaling activation and is supported by E-cad cleavage. Second, using an engineered cleavable form of E-cad, we demonstrate that sole extracellular E-cad truncation at the plasma membrane promotes apical extrusion. We propose that extracellular cleavage of E-cad generates a rapid change in cell-cell adhesion sufficient to drive apical cell extrusion. Whereas in normal epithelia, extrusion is followed by apoptosis, when combined to active oncogenic signaling, it is coupled to cell proliferation.
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14
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Hofmann G, Balic M, Dandachi N, Resel M, Schippinger W, Regitnig P, Samonigg H, Bauernhofer T. The predictive value of serum soluble E-cadherin levels in breast cancer patients undergoing preoperative systemic chemotherapy. Clin Biochem 2013; 46:1585-9. [DOI: 10.1016/j.clinbiochem.2013.06.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Revised: 06/06/2013] [Accepted: 06/11/2013] [Indexed: 11/26/2022]
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15
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Biomarkers in bladder cancer: translational and clinical implications. Crit Rev Oncol Hematol 2013; 89:73-111. [PMID: 24029603 DOI: 10.1016/j.critrevonc.2013.08.008] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2013] [Revised: 07/23/2013] [Accepted: 08/13/2013] [Indexed: 01/15/2023] Open
Abstract
Bladder cancer is associated with high recurrence and mortality rates. These tumors show vast heterogeneity reflected by diverse morphologic manifestations and various molecular alterations associated with these disease phenotypes. Biomarkers that prospectively evaluate disease aggressiveness, progression risk, probability of recurrence and overall prognosis would improve patient care. Integration of molecular markers with conventional pathologic staging of bladder cancers may refine clinical decision making for the selection of adjuvant and salvage therapy. In the past decade, numerous bladder cancer biomarkers have been identified, including various tumor suppressor genes, oncogenes, growth factors, growth factor receptors, hormone receptors, proliferation and apoptosis markers, cell adhesion molecules, stromal factors, and oncoproteins. Recognition of two distinct pathways for urothelial carcinogenesis represents a major advance in the understanding and management of this disease. Nomograms for combining results from multiple biomarkers have been proposed to increase the accuracy of clinical predictions. The scope of this review is to summarize the major biomarker findings that may have translational and clinical implications.
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Clinical Significance of Serum Soluble E-cadherin in Colorectal Carcinoma. J Surg Res 2012; 175:e67-73. [DOI: 10.1016/j.jss.2011.11.009] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2011] [Revised: 10/23/2011] [Accepted: 11/08/2011] [Indexed: 01/22/2023]
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Casado-Vela J, Gómez del Pulgar T, Cebrián A, Alvarez-Ayerza N, Lacal JC. Human urine proteomics: building a list of human urine cancer biomarkers. Expert Rev Proteomics 2011; 8:347-60. [PMID: 21679116 DOI: 10.1586/epr.11.26] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
In the last decade, several reports have focused on the identification and characterization of proteins present in urine. In an effort to build a list of proteins of interest as biomarkers, we reviewed the largest urine proteomes and built two updated lists of proteins of interest (available as supplementary tables). The first table includes a consensus list of 443 proteins found in urine by independent laboratories and reported on the top three largest urine proteomes currently published. This consensus list of proteins could serve as biomarkers to diagnose, monitor and manage a number of diseases. Here, we focus on a reduced list of 35 proteins with potential interest as cancer biomarkers in urine following two criteria: first, proteins previously detected in urine using bottom-up proteomic experiments, and second, those suggested as cancer protein biomarkers in human plasma. In an effort to standardize the information presented and its use in future studies, here we include the updated International Protein Index (v. 3.80) and primary Swiss-Prot accession numbers, official gene symbols and recommended full names. The main variables that influence urine proteomic experiments are also discussed.
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Affiliation(s)
- Juan Casado-Vela
- Translational Oncology Unit, Instituto de Investigaciones Biomédicas Alberto Sols, Spanish National Research Council (CSIC), 28029 Madrid, Spain
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Chung Y, Law S, Kwong DLW, Luk JM. Serum soluble E-cadherin is a potential prognostic marker in esophageal squamous cell carcinoma. Dis Esophagus 2011; 24:49-55. [PMID: 20807231 DOI: 10.1111/j.1442-2050.2010.01093.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
E-cadherin is a well-documented tumor suppressor with downregulated expression in many cancer types. Upon proteolytic cleavage, a soluble form of 80-kDa degradation fragment, known as soluble E-cadherin (s-Ecad), is present in circulation; its level in sera of cancer patients is significantly associated with metastasis, recurrence, and prognosis in some malignancies. The present study investigated the association of s-Ecad with clinicopathological characteristics of patients with esophageal squamous cell carcinoma (ESCC) and its prognostic significance. A cohort of 97 patients who underwent surgery alone (n= 56) or neoadjuvant chemoradiation therapy and surgery (CRT) (n= 41) was recruited for this study. Serum samples were collected at operation (surgery group) and pre- and post-CRT treatment (CRT group) for measurement of s-Ecad protein by enzyme linked immunosorbent assay. Serum s-Ecad levels were correlated with clinicopathological parameters as well as survival. Univariate analysis showed no significant relationship between serum s-Ecad level and clinicopathological parameters for all sets of samples. Survival analysis showed that in patients who had surgical resection only, those with s-Ecad levels equal to or below the median value survived significantly longer than those with levels above the median (median survival 25.6 vs. 14.1 months, P= 0.012). Multivariate analysis showed that pathological N stage, M stage, R category, and serum s-Ecad level were significant independent prognostic factors for ESCC patients who underwent surgery only. The hazard ratio for s-Ecad was 1.104 (95% CI: 1.026-1.187) and P= 0.008. Serum s-Ecad was detected in ESCC patients and its potential as an independent prognostic marker requires further investigation.
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Affiliation(s)
- Y Chung
- Department of Surgery, Division of Esophageal and Upper Gastrointestinal Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong
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19
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Craig SEL, Brady-Kalnay SM. Cancer cells cut homophilic cell adhesion molecules and run. Cancer Res 2010; 71:303-9. [PMID: 21084269 DOI: 10.1158/0008-5472.can-10-2301] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The term contact inhibition (CI) encompasses the cellular changes that result in cessation of cell migration and of proliferation due to signals transduced when one cell comes into physical contact with another cell. Cancer cells, however, do not contact inhibit. A molecular understanding of the loss of CI in cancer cells is important for understanding tumor progression. In this Perspective, we propose that the loss of CI observed in cancer cells is the result of extracellular proteolysis of transmembrane cell-cell cell adhesion molecules (CAM) in the tumor microenvironment. Proteolysis of homophilic cell-cell CAMs results in a shed extracellular fragment and released cytoplasmic fragment(s) that disrupts adhesion and induces signals that promote proliferation and/or migration. The importance of this observation in tumor progression is supported by the presence of the shed extracellular fragments of homophilic cell-cell CAMs in serum and tumor tissue of cancer patients suggesting that instead of acting as tumor suppressors, the shed CAM extracellular and cytoplasmic fragments actually function as oncogenes. The study of cell-cell CAM cleavage will provide important and novel means of diagnosing, imaging, and treating tumor progression.
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Affiliation(s)
- Sonya E L Craig
- Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio 44106-4960, USA
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20
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Sewpaul A, French JJ, Khoo TK, Kernohan M, Kirby JA, Charnley RM. Soluble E-cadherin: an early marker of severity in acute pancreatitis. HPB SURGERY : A WORLD JOURNAL OF HEPATIC, PANCREATIC AND BILIARY SURGERY 2009; 2009:397375. [PMID: 19421334 PMCID: PMC2674558 DOI: 10.1155/2009/397375] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2008] [Accepted: 02/18/2009] [Indexed: 12/17/2022]
Abstract
BACKGROUND/AIMS At present, there is no simple test for predicting severity in acute pancreatitis. We investigated the use of an assay of soluble E-cadherin (sE-cadherin). METHODS Concentrations of sE-cadherin, from 19 patients with mild acute pancreatitis, 7 patients with severe acute pancreatitis, 11 patients with other acute gastrointestinal pathologies, and 12 healthy subjects were measured using a commercially available sandwich ELISA kit based on two monoclonal antibodies specific to the extracellular fragment of human E-cadherin. Measurements were made at 12 hours or less from onset of pain and also at 24 and 48 hours after onset of pain. RESULTS Mean (standard deviation) concentration of sE-cadherin in patients with severe acute pancreatitis at <12 hours was 17780 ng/mL (7853), significantly higher than that of healthy volunteers 5180 ng/mL (1350), P = .0039, patients with other gastrointestinal pathologies 7358 ng/mL (6655), P = .0073, and also significantly higher than that of patients with mild pancreatitis, 7332 ng/mL (2843), P = .0019. DISCUSSION Serum sE-cadherin could be an early (within 12 hours) objective marker of severity in acute pancreatitis. This molecule warrants further investigation in the form of a large multicentre trial.
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Affiliation(s)
- A. Sewpaul
- HPB Surgical Unit, Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK
| | - J. J. French
- HPB Surgical Unit, Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK
| | - T. K. Khoo
- HPB Surgical Unit, Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK
| | - M. Kernohan
- HPB Surgical Unit, Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK
| | - J. A. Kirby
- Department of Surgery, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK
| | - R. M. Charnley
- HPB Surgical Unit, Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK
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21
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Chan AOO, Wong BCY. Deregulation of E-Cadherin in Precancerous Lesions and Gastric Cancer. THE BIOLOGY OF GASTRIC CANCERS 2009:377-388. [DOI: 10.1007/978-0-387-69182-4_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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22
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ADAM10-mediated E-cadherin release is regulated by proinflammatory cytokines and modulates keratinocyte cohesion in eczematous dermatitis. J Invest Dermatol 2008; 128:1737-46. [PMID: 18200054 DOI: 10.1038/sj.jid.5701242] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Acute eczema is an inflammatory skin disease characterized by the formation of small intraepidermal blisters, reduction of the adhesion molecule E-cadherin from the keratinocyte surface, and impaired keratinocyte cohesion. Here, we reveal that the disintegrin and metalloprotease ADAM10 is critically involved in regulating E-cadherin cell-surface expression in cultured primary human keratinocytes and in diseased human skin. Proinflammatory cytokines, transforming growth factor-beta, and lipopolysaccharide led to increased release of soluble E-cadherin by activating mitogen-activated protein kinase signaling in cultured keratinocytes. Moreover, these stimuli decreased the amount of pro-ADAM10 and increased the level of the active protease, leading to loss of E-cadherin from the cell surface and decreased keratinocyte cohesion. In situ examination and immunoblot analyses of E-cadherin and ADAM10 expression in lesional skin of eczema revealed that the reduction of E-cadherin expression in areas of blister formation closely correlated with increased level of ADAM10 expression and elevated E-cadherin shedding. Our data suggest that ADAM10-mediated E-cadherin proteolysis leads to the impaired cohesion of keratinocytes observed in eczematous dermatitis and provide previously unreported insights into the understanding of the molecular mechanisms involved in inflammatory diseases with loss in epithelial integrity.
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23
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Al Kassam D, Álvarez Marcos C, Blanco I, de Los Toyos JR, Luis Llorente J. Valor diagnóstico de los marcadores E-cadherina, MMP-9, MMP-13 activada y de los anticuerpos anti-p53 en el carcinoma escamoso de cabeza y cuello. Med Clin (Barc) 2007; 129:761-5. [DOI: 10.1157/13113764] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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24
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Soluble cadherins as cancer biomarkers. Clin Exp Metastasis 2007; 24:685-97. [PMID: 17952616 DOI: 10.1007/s10585-007-9104-8] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2007] [Accepted: 09/19/2007] [Indexed: 01/17/2023]
Abstract
Molecular activities, regulating a balanced tissue organisation, are frequently disturbed during cancer progression. These include protein ectodomain shedding, a post-translational process that substantially changes the functional properties of the substrate protein. In comparison with normal epithelia, cancer cells almost invariably show diminished cadherin-mediated intercellular adhesion. This review will address cadherin ectodomain shedding and its functional consequence in normal physiology and in the tumor environment. Soluble cadherin fragments may retain specific biological activities during cancer cell invasion, angiogenesis and perineural invasion. When diffusion barriers disappear, soluble cadherins are detected in sera from cancer patients. Soluble N-(neural) cadherin may represent a novel diagnosis/prognostic biomarker showing a correlation with PSA in sera of prostate cancer patients. Furthermore, therapeutic monitoring in pancreas adenomacarcinoma revealed a correlation between circulating soluble N-cadherin and CA 19-9. A better understanding of cadherin regulation in cancer progression will likely increase our awareness of the importance of the combinatorial signals that regulate tissue integrity and eventually result in the identification of new therapeutics targeting cadherins.
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25
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Masterson J, O'Dea S. Posttranslational truncation of E-cadherin and significance for tumour progression. Cells Tissues Organs 2007; 185:175-9. [PMID: 17587823 DOI: 10.1159/000101318] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Stable intraepithelial adhesion complexes are essential for the maintenance of epithelial integrity. Alterations in these complexes are key events in the development and progression of many diseases. One of the major proteins involved in maintaining epithelial cell-cell adhesion is the cell-adhesion junction protein E-cadherin, a member of the cadherin family of transmembrane adhesion proteins. E-cadherin is involved in many cellular processes including morphogenesis, adhesion, recognition, communication and oncogenesis. Inactivation of its adhesive properties is often a key step in tumour progression and metastasis, leading to its recent description as a tumour suppressor gene. Mutations of the E-cadherin gene CDH1 in gastric and mammary cancers have been well documented and reports of transcriptional repression during tumour progression are increasing. This review examines the role of posttranslational truncation of E-cadherin in cancer cells focusing on implications for tumour progression. The various proteins involved in the directed cleavage of E-cadherin and consequences of these truncations are discussed.
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Affiliation(s)
- Joanne Masterson
- Institute of Immunology, Biology Department, National University of Ireland Maynooth, Maynooth, Ireland.
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26
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Jäger T, Szarvas T, vom Dorp F, Börgermann C, Schenck M, Schmid KW, Rübben H. Einsatz der Siliziumchiptechnologie zur Detektion von Tumormarkern auf Proteinbasis beim Harnblasenkarzinom. Urologe A 2007; 46:1152-6. [PMID: 17593336 DOI: 10.1007/s00120-007-1429-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The protein structure of human tumor tissue has a significant influence on the molecular attributes. It was demonstrated that the individual prognosis of tumor patients is among other things dependent on molecular tumor tissue characteristics.A promising marker is E-cadherin, an adhesion glycoprotein which plays a central role in the mediation of cell-cell contacts. Aberrant E-cadherin expressions were described in several tumors such as in bladder cancer. This was also found to be correlated with tumor invasion and survival. There are hardly any fast, quantitative and easily automated protein assays in everyday practice which can analyze several markers at the same time. With silicon chip technology we have a new detection and measurement method which makes it possible to give a quantitative analysis of numerous different proteins in tissue, urine, or serum in a few minutes.
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Affiliation(s)
- T Jäger
- Klinik für Urologie, Universitätsklinikum, Hufelandstrasse 55, 45147 Essen.
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27
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Kleiner S, Faisal A, Nagamine Y. Induction of uPA gene expression by the blockage of E-cadherin via Src- and Shc-dependent Erk signaling. FEBS J 2007; 274:227-40. [PMID: 17222183 DOI: 10.1111/j.1742-4658.2006.05578.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Loss of E-cadherin-mediated cell-cell adhesion and expression of proteolytic enzymes characterize the transition from benign lesions to invasive, metastatic tumor, a rate-limiting step in the progression from adenoma to carcinoma in vivo. A soluble E-cadherin fragment found recently in the serum and urine of cancer patients has been shown to disrupt cell-cell adhesion and to drive cell invasion in a dominant-interfering manner. Physical disruption of cell-cell adhesion can be mimicked by the function-blocking antibody Decma. We have shown previously in MCF7 and T47D cells that urokinase-type plasminogen activator (uPA) activity is up-regulated upon disruption of E-cadherin-dependent cell-cell adhesion. We explored the underlying molecular mechanisms and found that blockage of E-cadherin by Decma elicits a signaling pathway downstream of E-cadherin that leads to Src-dependent Shc and extracellular regulated kinase (Erk) activation and results in uPAgene activation. siRNA-mediated knockdown of endogenous Src-homology collagen protein (Shc) and subsequent expression of single Shc isoforms revealed that p46(Shc) and p52(Shc) but not p66(Shc) were able to mediate Erk activation. A parallel pathway involving PI3K contributed partially to Decma-induced Erk activation. This report describes that disruption of E-cadherin-dependent cell-cell adhesion induces intracellular signaling with the potential to enhance tumorigenesis and, thus, offers new insights into the pathophysiological mechanisms of tumor development.
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Affiliation(s)
- Sandra Kleiner
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
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28
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Polanski M, Anderson NL. A list of candidate cancer biomarkers for targeted proteomics. Biomark Insights 2007; 1:1-48. [PMID: 19690635 PMCID: PMC2716785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
We have compiled from literature and other sources a list of 1261 proteins believed to be differentially expressed in human cancer. These proteins, only some of which have been detected in plasma to date, represent a population of candidate plasma biomarkers that could be useful in early cancer detection and monitoring given sufficiently sensitive specific assays. We have begun to prioritize these markers for future validation by frequency of literature citations, both total and as a function of time. The candidates include proteins involved in oncogenesis, angiogenesis, development, differentiation, proliferation, apoptosis, hematopoiesis, immune and hormonal responses, cell signaling, nucleotide function, hydrolysis, cellular homing, cell cycle and structure, the acute phase response and hormonal control. Many have been detected in studies of tissue or nuclear components; nevertheless we hypothesize that most if not all should be present in plasma at some level. Of the 1261 candidates only 9 have been approved as "tumor associated antigens" by the FDA. We propose that systematic collection and large-scale validation of candidate biomarkers would fill the gap currently existing between basic research and clinical use of advanced diagnostics.
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Affiliation(s)
- Malu Polanski
- The Plasma Proteome Institute, P.O. Box: 53450, Washington DC, 20009-3450, USA
| | - N. Leigh Anderson
- The Plasma Proteome Institute, P.O. Box: 53450, Washington DC, 20009-3450, USA
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29
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Abstract
We have compiled from literature and other sources a list of 1261 proteins believed to be differentially expressed in human cancer. These proteins, only some of which have been detected in plasma to date, represent a population of candidate plasma biomarkers that could be useful in early cancer detection and monitoring given sufficiently sensitive specific assays. We have begun to prioritize these markers for future validation by frequency of literature citations, both total and as a function of time. The candidates include proteins involved in oncogenesis, angiogenesis, development, differentiation, proliferation, apoptosis, hematopoiesis, immune and hormonal responses, cell signaling, nucleotide function, hydrolysis, cellular homing, cell cycle and structure, the acute phase response and hormonal control. Many have been detected in studies of tissue or nuclear components; nevertheless we hypothesize that most if not all should be present in plasma at some level. Of the 1261 candidates only 9 have been approved as "tumor associated antigens" by the FDA. We propose that systematic collection and large-scale validation of candidate biomarkers would fill the gap currently existing between basic research and clinical use of advanced diagnostics.
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Affiliation(s)
- Malu Polanski
- The Plasma Proteome Institute, P.O. Box: 53450, Washington DC, 20009-3450, USA
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30
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Reiss K, Ludwig A, Saftig P. Breaking up the tie: Disintegrin-like metalloproteinases as regulators of cell migration in inflammation and invasion. Pharmacol Ther 2006; 111:985-1006. [PMID: 16626807 DOI: 10.1016/j.pharmthera.2006.02.009] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2006] [Accepted: 02/28/2006] [Indexed: 12/20/2022]
Abstract
Cell adhesion and cell migration are essential for a variety of important events in both embryonic development and in the adult organism. Cell adhesion molecules (CAM) like selectins, immunoglobulin superfamily members, integrins, and cadherins undergo diverse mechanisms of regulation. Dysregulation of adhesion can lead to pathological processes, including inflammatory diseases or tumor metastasis either by disrupting the normal anchorage, thereby altering cell movement and regulatory signalling, or by promoting inappropriate temporal and spatial adhesion. An increasing body of evidence has emerged showing that members of the a disintegrin and metalloproteinase (ADAM) family critically contribute to the regulation of CAM functions. While the disintegrin domain can interact with integrins and mediate adhesion, the metalloproteinase domain can mediate anti-adhesive functions by cleaving the membrane bound adhesion molecules. This "shedding" process leads to the release of often still functional soluble ectodomains and can additionally influence intracellular cell signalling pathways. Several soluble CAMs have been detected in vitro and in vivo. Some of them are strongly increased in inflammatory diseases or in the serum of cancer patients. Therefore the level of soluble CAMs but also the expression of the metalloproteinases responsible for their release might provide prognostic information. It could also be useful for monitoring malignant disease stages and for evaluating the effectiveness of various therapeutic approaches. Moreover, metalloproteases of the ADAM family are emerging as promising targets for new therapeutic options.
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Affiliation(s)
- Karina Reiss
- Biochemical Institute, Christian-Albrecht-University Kiel, Olshausenstr. 40, D-24098 Kiel, Germany
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31
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Coskun U, Sancak B, Sen I, Bukan N, Tufan MA, Gülbahar O, Sozen S. Serum P-selectin, soluble vascular cell adhesion molecule-I (s-VCAM-I) and soluble intercellular adhesion molecule-I (s-ICAM-I) levels in bladder carcinoma patients with different stages. Int Immunopharmacol 2006; 6:672-7. [PMID: 16504931 DOI: 10.1016/j.intimp.2005.10.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2005] [Revised: 09/11/2005] [Accepted: 10/19/2005] [Indexed: 11/30/2022]
Abstract
Adhesion molecules are thought to have a role in the host defense against carcinogenesis. In this study, we measured serum platelet-(P-) selectin, soluble vascular cell adhesion molecule-I (s-VCAM-I), and soluble intercellular adhesion molecule-I (s-ICAM-I) levels in 51 sequential bladder cancer patients at our urology clinic and 8 controls. Serum levels of P-selectin, s-VCAM-I and s-ICAM-I were significantly higher in all patients than controls. Serum P-selectin and s-ICAM-I levels did not differ based on tumor (T) stage and tumor grade, whereas serum levels of s-VCAM-I were significantly higher in patients with muscle invasive tumors than those with superficial tumors. Further, s-VCAM-I levels correlated with T stage. In conclusion, significantly increased P-selectin, s-VCAM-I, and s-ICAM-I levels were observed in patients with bladder cancer, and s-VCAM-I levels correlated with T stage. Thus, we suggest that the analysis of serum s-VCAM-I levels may provide a prognostic test for T stage and bladder cancer progression during and/or following therapy.
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Affiliation(s)
- Ugur Coskun
- Gazi University Medical School, Department of Medical Oncology, Ankara, Turkey.
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Abstract
Cadherin is an adhesion molecule and a superfamily of calcium-mediated membrane glycoproteins. E-cadherin is the prototype of the class E-cadherin that links to catenins to form the cytoskeleton. Recent evidence has shown that E-cadherin not only acts as an adhesive, but also plays important roles in growth development and carcinogenesis. It has been recently viewed as an invasion as well as a growth suppressor gene. This review summarizes the recent discoveries on E-cadherin and its role in gastric cancer. In particular, our work on E-cadherin in gastric cancer, including its relation with Helicobacter pylori and clinical applications, are described in detail.
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Affiliation(s)
- Annie On On Chan
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
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33
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Kuefer R, Hofer MD, Zorn CSM, Engel O, Volkmer BG, Juarez-Brito MA, Eggel M, Gschwend JE, Rubin MA, Day ML. Assessment of a fragment of e-cadherin as a serum biomarker with predictive value for prostate cancer. Br J Cancer 2005; 92:2018-23. [PMID: 15870707 PMCID: PMC2361796 DOI: 10.1038/sj.bjc.6602599] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
In prostate cancer, biomarkers may provide additional value above standard clinical and pathology parameters to predict outcome after specific therapy. The purpose of this study is to evaluate an 80 kDa fragment of the cell adhesion molecule e-cadherin as a serum biomarker. A broad spectrum of prostate cancer serum samples, representing different stages of prostate cancer disease, including benign prostatic hyperplasia (BPH), localised (Loc PCA) and metastatic prostate cancer (Met PCA), was examined for the cleaved product. There is a significant difference in the expression level of the 80 kDa fragment in the serum of healthy individuals vs patients with BPH and between BPH vs Loc PCA and Met PCA (P<0.001). Highest expression levels are observed in advanced metastatic disease. In the cohort of Loc PCA cases, there was no association between the 80 kDa serum concentration and clinical parameters. Interestingly, patients with an 80 kDa level of >7.9 μg l−1 at the time of diagnosis have a 55-fold higher risk of biochemical failure after surgery compared to those with lower levels. This is the first report of the application of an 80 kDa fragment of e-cadherin as a serum biomarker in a broad spectrum of prostate cancer cases. At an optimised cutoff, high expression at the time of diagnosis is associated with a significantly increased risk of biochemical failure, potentially supporting its use for a tailored follow-up protocol for those patients.
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Affiliation(s)
- R Kuefer
- Department of Urology, Faculty of Medicine, University of Ulm, Prittwitzstrasse 43, Ulm 89075, Germany.
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Shariat SF, Matsumoto K, Casella R, Jian W, Lerner SP. Urinary levels of soluble e-cadherin in the detection of transitional cell carcinoma of the urinary bladder. Eur Urol 2005; 48:69-76. [PMID: 15967254 DOI: 10.1016/j.eururo.2005.02.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2004] [Accepted: 02/16/2005] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To test the hypothesis that elevated urinary levels of soluble E-cadherin (sE-cadherin) would aid in the detection of transitional cell carcinoma (TCC) of the urinary bladder. METHODS We performed sE-cadherin staining of one murine (MBT2) and four human (RT4, 5637, T24, and TCCSUP) bladder cancer cell lines. sE-cadherin levels were also determined in voided urine of 188 consecutive subjects at risk for TCC recurrence, 31 patients with other uro-pathologic conditions, and 10 healthy subjects using a commercially-available ELISA kit. sE-cadherin was analyzed continuously and categorically on the basis of its median distribution. RESULTS Moderately and poorly differentiated bladder cancer cell lines had decreased cellular E-cadherin expression, whereas RT4, a well differentiated cell line, had preserved expression. All cell lines had measurable sE-cadherin levels in their conditioned media. The area under the ROC curve of sE-cadherin for the detection of TCC was 0.719 (95%CI, 0.637-0.801; p<0.001). Higher levels of sE-cadherin were associated with positive cytology results (p=0.012) and muscle invasive tumor stage (p=0.009). Urinary sE-cadherin was more sensitive, but less specific than urinary cytology for the detection of bladder TCC. In a multivariable logistic regression analysis, higher sE-cadherin and positive cytology were both associated with an increased risk of bladder TCC (p=0.048 and p<0.001, respectively). Combination of cytology and sE-cadherin allowed categorization of patients into three significantly different risk groups for bladder cancer. Adjustment of sE-cadherin for urinary creatinine levels did not affect any of the outcomes. CONCLUSIONS Urinary level of sE-cadherin may add information to cytology in the detection of bladder TCC.
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Affiliation(s)
- Shahrokh F Shariat
- Department of Urology, University of Texas Southwestern Medical School; 5323 Harry Hines Blvd, Dallas, Texas 75390-9110, USA.
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Gontero P, Banisadr S, Frea B, Brausi M. Metastasis markers in bladder cancer: a review of the literature and clinical considerations. Eur Urol 2005; 46:296-311. [PMID: 15306099 DOI: 10.1016/j.eururo.2004.04.001] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/01/2004] [Indexed: 12/22/2022]
Abstract
Cancer invasion and metastasis develop through a sequence of processes involving loss of cell-cell and cell-matrix adhesions, proteolysis and induction of angiogenesis. We reviewed the current literature on the molecules that have been shown to play a significant role in these three steps of metastatisation in bladder cancer (BC) cells and their host microenvironment. Particular emphasis was given to markers that are assessable through immunohistochemistry and for which an additional prognostic value over the TNM variables has been recognized, in order to identify a subset of tumour markers readily available for application in daily clinical practice. We conclude that markers such as E-cadherin, Sialosyl-LeX, laminin, collagen IV, TSP-1 and MVD are useful prognostic markers, alpha, beta, and gamma catenin, MMP-2 and -9, uPAR, PD-ECGF and Bfgf can be considered potentially useful, while research on CD44, MMP-1 and -3, uPA, cathepsin D and VEGF has proved inconclusive. Further research in this field should concentrate on the molecules listed in the first group.
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Affiliation(s)
- Paolo Gontero
- Department of Urology, Università del Piemonte Orientale, Novara, Italy.
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Wilmanns C, Grossmann J, Steinhauer S, Manthey G, Weinhold B, Schmitt-Gräff A, von Specht BU. Soluble serum E-cadherin as a marker of tumour progression in colorectal cancer patients. Clin Exp Metastasis 2004; 21:75-8. [PMID: 15065605 DOI: 10.1023/b:clin.0000017204.38807.22] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
A pilot study was conducted to determine the concentrations of soluble serum E-cadherin in 36 patients with colorectal cancer or a high-grade dysplasia by the use of an ELISA technique. The results were compared with staging characteristics and concentrations of routine serum carcinoembryonic antigen (CEA). Sixteen patients with benign diseases and nine healthy volunteers served as internal or negative controls. Tumour specimens from seven patients were analysed by immunohistochemistry to compare concentrations of soluble serum E-cadherin with patterns of cell-bound E-cadherin or beta-catenin. Serum E-cadherin concentrations were increased in colorectal cancer patients (P = 0.009), but also in benign disease controls (P = 0.005), correlating with the T- (P < 0.05), but not N- or M-stage, and with serum CEA (P = 0.002) in case of existing liver metastases. Compared with other staining patterns, concentrations of soluble serum E-cadherin were higher in case of an exclusive membrane-bound localization of cellular beta-catenin (P = 0.071). The results suggest marker characteristics of soluble serum E-cadherin in colorectal cancer patients, but lacking specificity argues against a routine clinical use.
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Affiliation(s)
- C Wilmanns
- Department of Surgery, Kreisklinikum Donaueschingen, Donaueschingen, Germany.
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Matsumoto K, Shariat SF, Casella R, Wheeler TM, Slawin KM, Lerner SP. Preoperative Plasma Soluble E-Cadherin Predicts Metastases to Lymph Nodes and Prognosis in Patients Undergoing Radical Cystectomy. J Urol 2003; 170:2248-52. [PMID: 14634390 DOI: 10.1097/01.ju.0000094189.93805.17] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE We have previously reported that high urinary levels of soluble E-cadherin (sE-cadherin) are associated with an increased risk of bladder cancer. We determined whether plasma levels of sE-cadherin are associated with bladder cancer stage and prognosis. MATERIALS AND METHODS The study group consisted of 50 patients who underwent radical cystectomy for muscle invasive cancer or intravesical therapy refractory Tis, Ta, or T1 bladder cancer; and 40 men without cancer. Preoperative plasma levels of sE-cadherin were measured using a commercially available enzyme-linked immunosorbent assay kit. RESULTS Plasma sE-cadherin was higher in patients with bladder cancer than in healthy subjects (p <0.0001) and it was elevated in patients with metastases to regional and distant lymph nodes (p = 0.019 and 0.024, respectively). When adjusted for the effects of clinical stage and grade, preoperative sE-cadherin was independently associated with metastases to regional lymph nodes (p = 0.028) and disease progression (p = 0.006) but not with bladder cancer mortality. In postoperative models preoperative sE-cadherin and lymph node metastases were associated with disease progression (p = 0.017 and 0.042, respectively) after adjusting for the effects of pathological stage, grade and lymphovascular invasion but only lymph node metastases were associated with cancer specific mortality (p = 0.007). CONCLUSIONS Higher plasma sE-cadherin is associated with bladder cancer. Higher preoperative plasma sE-cadherin has the potential to identify patients with metastases to regional and distant lymph nodes who are at increased risk for failure of local therapy with curative intent. These patients may benefit from more extensive lymph node dissection and/or combined modality treatment regimens.
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Affiliation(s)
- Kazumasa Matsumoto
- Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030, USA
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38
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Nawrocki-Raby B, Gilles C, Polette M, Bruyneel E, Laronze JY, Bonnet N, Foidart JM, Mareel M, Birembaut P. Upregulation of MMPs by soluble E-cadherin in human lung tumor cells. Int J Cancer 2003; 105:790-5. [PMID: 12767064 DOI: 10.1002/ijc.11168] [Citation(s) in RCA: 97] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Loss of E-cadherin/catenin mediated cell-cell adhesion and overexpression of matrix metalloproteinases (MMPs) are largely involved in tumor invasion. It has been recently shown that high levels of a soluble 80 kDa fragment of E-cadherin, resulting from a cleavage by MMPs, are found in serum and in urine from cancer patients. Additionally, this soluble E-cadherin (sE-CAD) promotes cell invasion into chick heart and into collagen type I gels. The aim of our study was to examine the mechanism of sE-CAD-induced cell invasion. Since MMPs play a crucial role in invasion, we looked for induction of MMPs by sE-CAD in noninvasive human lung tumor cells 16HBE. An induction of MMP-2, MMP-9 and MT1-MMP expression was observed both at the mRNA and at the protein level in the presence of sE-CAD (in conditioned medium form or in E-cadherin HAV peptide form). No induction of MMP-1, -3 and -7 or variation of the levels of their inhibitors, TIMP-1 and TIMP-2, were detected. The biologic relevance of the sE-CAD-induced MMP upregulation was tested by demonstrating that sE-CAD promotes in vitro cell invasion in a modified Boyden chamber assay. These data provide new insight into mechanisms of tumor invasion by ectodomain shedding of the cell-cell adhesion molecule E-cadherin.
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da Silva Tatley F, Aldwell FE, Dunbier AK, Guilford PJ. N-terminal E-cadherin peptides act as decoy receptors for Listeria monocytogenes. Infect Immun 2003; 71:1580-3. [PMID: 12595481 PMCID: PMC148857 DOI: 10.1128/iai.71.3.1580-1583.2003] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The observation that E-cadherin is the principal epithelial receptor for the bacterial pathogen Listeria monocytogenes led us to investigate whether N-terminal fragments of E-cadherin containing the L. monocytogenes binding domain could inhibit entry of the bacteria into cultured epithelial cells. Here we demonstrate that a conditioned medium from a gastric cancer cell line (Kato III) that carries a truncating CDH-1 mutation 3' of the L. monocytogenes binding domain can inhibit the uptake of the bacteria into Caco-2 cells. The inhibitory activity of the Kato III conditioned medium could be mimicked by incubation of the bacteria with a recombinant 26-kDa N-terminal E-cadherin peptide prior to infection. Furthermore, these data suggest that cleavage of the 80-kDa extracellular domain of E-cadherin from the cell surface may provide an innate form of pathogen defense by acting as a decoy receptor for L. monocytogenes.
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Affiliation(s)
- Fernanda da Silva Tatley
- Cancer Genetics Laboratory, Department of Biochemistry, Department of Microbiology, University of Otago, Dunedin, Aotearoa, New Zealand
| | - Frank E. Aldwell
- Cancer Genetics Laboratory, Department of Biochemistry, Department of Microbiology, University of Otago, Dunedin, Aotearoa, New Zealand
| | - Anita K. Dunbier
- Cancer Genetics Laboratory, Department of Biochemistry, Department of Microbiology, University of Otago, Dunedin, Aotearoa, New Zealand
| | - Parry J. Guilford
- Cancer Genetics Laboratory, Department of Biochemistry, Department of Microbiology, University of Otago, Dunedin, Aotearoa, New Zealand
- Corresponding author. Mailing address: Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, P.O. Box 56, Dunedin, New Zealand. Phone: 64-3-4795803. Fax: 64-3-479580. E-mail:
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41
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Soler AP, Russo J, Russo IH, Knudsen KA. Soluble fragment of P-cadherin adhesion protein found in human milk. J Cell Biochem 2002. [DOI: 10.1002/jcb.10126] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Ryniers F, Stove C, Goethals M, Brackenier L, Noë V, Bracke M, Vandekerckhove J, Mareel M, Bruyneel E. Plasmin produces an E-cadherin fragment that stimulates cancer cell invasion. Biol Chem 2002; 383:159-65. [PMID: 11928810 DOI: 10.1515/bc.2002.016] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Matrix metalloproteases from the cell surface cleave an 80 kDa E-cadherin fragment (sE-CAD) that induces invasion of cancer cells into collagen type I and inhibits cellular aggregation. Conditioned media from MDCKts.srcCl2 cells at 40 degrees C and 35 degrees C, PCm.src5 and COLO-16 cells at 37 degrees C contained spontaneously released sE-CAD; these 48 h old conditioned media were capable of inhibiting E-cadherin functions in a paracrine way. Here we show direct cleavage of the extracellular domain of E-cadherin by the serine protease plasmin. sE-CAD released by plasmin inhibits E-cadherin functions as evidenced by induction of invasion into collagen type I and inhibition of cellular aggregation. This functional inhibition by sE-CAD was reversed by aprotinin or by immunoadsorption on protein Sepharose 4 fast flow beads with antibodies against the extracellular part of E-cadherin. Our results demonstrate that plasmin produces extracellular E-cadherin fragments which regulate E-cadherin function in cells containing an intact E-cadherin/catenin complex.
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Affiliation(s)
- Filip Ryniers
- Laboratory of Experimental Cancerology, Department of Radiotherapy and Nuclear Medicine, University Hospital Ghent, Belgium
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Mason MD, Davies G, Jiang WG. Cell adhesion molecules and adhesion abnormalities in prostate cancer. Crit Rev Oncol Hematol 2002; 41:11-28. [PMID: 11796229 DOI: 10.1016/s1040-8428(01)00171-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Prostate cancer, the leading male cancer in Western countries, has accelerated in its incidence in the past decade. Patients with prostate cancer frequently have a poor prognosis as a result of local or distant spread of cancer. This review summarises some of the recent progress made in understanding the biology of cancer metastasis with a special emphasis on the role of cell adhesion molecules and adhesion abnormalities. The molecular and cellular function of cell adhesion molecules, their role in cancer and cancer progression, the clinical impact of these molecules, and therapeutic considerations are also discussed.
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Affiliation(s)
- Malcolm D Mason
- Department of Clinical Oncology, University of Wales College of Medicine, Health Park, Cardiff, UK.
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Abstract
The current pathological and clinical parameters provide important prognostic information, yet still have limited ability to predict the true malignant potential of most bladder tumors. In the last years, investigation of the basic mechanisms involved in carcinogenesis and tumor progression by molecular biology has provided a host of markers which are of potential diagnostic or prognostic value for bladder carcinoma. These markers may serve as tools for early and accurate prediction of tumor recurrence, progression and development of metastases and for prediction of response to therapy. The precise prediction of tumor biological behavior would facilitate treatment selection for patients who may benefit from radical surgical treatment or adjuvant therapy. We provide a current, comprehensive review of the literature on bladder tumor markers with a special emphasis on their prognostic potential. The literature suggests that currently no single marker is able to accurately predict the clinical course of bladder tumors and thus would serve as a reliable prognosticator. A combination of prognostic markers could predict which superficial tumors need an aggressive form of therapy and which invasive tumors require adjuvant therapy. Altogether, the most promising markers are, at this point, Ki-67 and p53 expression as well as matrixmetalloproteinase complex and angiogenesis.
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Affiliation(s)
- I Kausch
- Department of Urology, Research Center Borstel, Medical University of Lübeck, Germany
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Chan AO, Lam SK, Chu KM, Lam CM, Kwok E, Leung SY, Yuen ST, Law SY, Hui WM, Lai KC, Wong CY, Hu HC, Lai CL, Wong J. Soluble E-cadherin is a valid prognostic marker in gastric carcinoma. Gut 2001; 48:808-11. [PMID: 11358900 PMCID: PMC1728335 DOI: 10.1136/gut.48.6.808] [Citation(s) in RCA: 69] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Gastric cancer remains a major cause of cancer mortality globally but no good prognostic tumour marker is available. Soluble fragment of E-cadherin protein has been reported to increase in the sera of patients with cancer and recently was found to be elevated in 67% of patients with gastric cancer. AIMS To investigate if serum soluble E-cadherin is a valid prognostic marker in gastric cancer. METHODS Concentrations of soluble E-cadherin from 116 patients with histologically confirmed gastric adenocarcinoma and 40 healthy subjects were measured using an immunoenzymometric method with a commercially available sandwich ELISA kit based on monoclonal antibodies. RESULTS The logarithm of the means of soluble E-cadherin concentration was significantly higher in patients with gastric cancers (mean 3.85 (SD 0.28)) than in healthy subjects (3.71 (0.18)) (p=0.001), and in palliative/conservatively treated cancers (3.91 (0.35)) than in operable cancers (3.78 (0.19)) (p=0.015). The logarithm of the concentrations correlated with tumour size (p=0.032) and carcinoembryonic antigen concentrations (p=0.001). The cut off value calculated from discriminant analysis on operability and inoperability/palliative treatment was 7025 ng/ml. Soluble E-cadherin concentrations higher than this cut off value predicted tumour (T4) depth invasion (p=0.020, confidence interval (CI) 1.008-1.668) and palliative/conservative treatment (p=0.023, CI 1.038-2.514). In contrast, the relative risks for lymph node (N2) metastasis, distant metastasis, and stage III/IV disease were 1.41, 1.33, and 1.55 respectively, despite not reaching statistical significance. CONCLUSION Serum soluble E-cadherin is a potential valid prognostic marker for gastric cancer. A high concentration predicts palliative/conservative treatment and T4 invasion.
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Affiliation(s)
- A O Chan
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong
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Noë V, Fingleton B, Jacobs K, Crawford HC, Vermeulen S, Steelant W, Bruyneel E, Matrisian LM, Mareel M. Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci 2001; 114:111-118. [PMID: 11112695 DOI: 10.1242/jcs.114.1.111] [Citation(s) in RCA: 437] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The function of many transmembrane molecules can be altered by cleavage and subsequent release of their ectodomains. We have investigated ectodomain cleavage of the cell-cell adhesion and signal-transducing molecule E-cadherin. The E-cadherin ectodomain is constitutively shed from the surface of MCF-7 and MDCKts.srcC12 cells in culture. Release of the 80 kDa soluble E-cadherin fragment is stimulated by phorbol-12-myristate-13-acetate and is inhibited by overexpression of the tissue inhibitor of metalloproteinases-2. The metalloproteinases matrilysin and stromelysin-1 both cleave E-cadherin at the cell surface and release sE-CAD into the medium. The soluble E-cadherin fragment thus released inhibits E-cadherin functions in a paracrine way, as indicated by induction of invasion into collagen type I and inhibition of E-cadherin-dependent cell aggregation. Our results, therefore, suggest a novel mechanism by which metalloproteinases can influence invasion.
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Affiliation(s)
- V Noë
- Laboratory of Experimental Cancerology, Department of Radiotherapy and Nuclear Medicine, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium
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48
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Abstract
Progress of molecular biology with regard to etiopathogeny of tumours in general, and cancer of the bladder in particular, is taking place at such a vertiginous pace that practising urologists find themselves overwhelmed in terms of their ability to learn and keep updated in so complex a subject. The understanding of certain molecular factors with critical influence on the formation, growth and progression of a tumour of the bladder, is forcing us to make unbiased assessments on the role they will play in the evolution and survival of this neoplasia. It is anticipate they will be much more reliable than traditionally established morphological factors such as grade and stage. We also include a literature review with an analysis and elucidation of the role played by oncogenes, tumor suppressor genes, vascular density markers, telomerase etc., in the formation and growth of cancer of the bladder and their likely relationships with already established clinico-pathological factors.
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Abstract
BACKGROUND The E-cadherin-catenin complex plays a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture. Perturbation in the expression or function of this complex results in loss of intercellular adhesion, with possible consequent cell transformation and tumour progression. Recently, much progress has been made in understanding the interaction between the different components of this protein complex and how this cell-cell adhesion complex is modulated in cancer cells. METHODS This is an update of the role of the E-cadherin-catenin complex in human cancers. It emphasizes new features and the possible role of the complex in clinical practice, discussed in the light of 165 references obtained from the Medline database from 1995 to 1999. RESULTS More evidence is now appearing to suggest that disturbance in protein-protein interaction in the E-cadherin-catenin adhesion complex is one of the main events in the early and late steps of cancer development. An inverse correlation is found between expression of the E-cadherin-catenin complex and the invasive behaviour of tumour cells. Therefore, E-cadherin-catenin may become a significant prognostic marker for tumour behaviour. Besides its role in establishing tight cell-cell adhesion, beta- catenin plays a major role in cell signalling and promotion of neoplastic growth. This suggests its dual role as a tumour suppressor and as an oncogene in human cancers. CONCLUSION Recent developments show that the E-cadherin-catenin complex is more than a 'sticky molecular complex'. Further studies may yield greater insight into the early molecular interactions critical to the initiation and progression of tumours. This should aid the development of novel strategies for both prevention and treatment of cancer.
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Affiliation(s)
- B P Wijnhoven
- Departments of Surgery and Pathology, Erasmus University Medical Centre, Rotterdam, The Netherlands
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Popov Z, Gil-Diez de Medina S, Lefrere-Belda MA, Hoznek A, Bastuji-Garin S, Abbou CC, Thiery JP, Radvanyi F, Chopin DK. Low E-cadherin expression in bladder cancer at the transcriptional and protein level provides prognostic information. Br J Cancer 2000; 83:209-14. [PMID: 10901372 PMCID: PMC2363483 DOI: 10.1054/bjoc.2000.1233] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
We studied E-cadherin down-regulation at the protein level in frozen sections of 111 bladder tumours and 13 normal bladder specimens by means of immunohistochemistry, and at the mRNA level by semi-quantitative RT-PCR in 40 of the same tumours. Results indicate that E-cadherin expression detected by immunohistochemistry correlated with both stage and grade (P < 0.0001 and P < 0.001, respectively). Analysis of recurrence, progression and survival over a mean period of 36 months after surgery in the entire cohort showed that abnormal E-cadherin immunoreactivity correlated strongly with poor outcome (log-rank test: P = 0.001, P = 0.0001 and P = 0.0003, respectively). In multistep logistic regression analysis, only E-cadherin status and stage had significant additional prognostic value (P= 0.008 and OR = 0.2; P= 0.03 and OR = 3.6, respectively). Survival estimates derived from RT-PCR transcript quantification differed significantly for low and high expression (log-rank test: P = 0.0006). These results suggest that the alteration occurs at the transcriptional level and support the clinical and biological relevance of cell adhesion molecules in bladder cancer.
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Affiliation(s)
- Z Popov
- Centre de Recherches Chirurgicales, EMI-INSERM 99-09 Département de Santé Publique et de Pathologie, Hôpital Henri Mondor, Créteil, France
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