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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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Zhou Y, Tao L, Qiu J, Xu J, Yang X, Zhang Y, Tian X, Guan X, Cen X, Zhao Y. Tumor biomarkers for diagnosis, prognosis and targeted therapy. Signal Transduct Target Ther 2024; 9:132. [PMID: 38763973 PMCID: PMC11102923 DOI: 10.1038/s41392-024-01823-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 03/07/2024] [Accepted: 04/02/2024] [Indexed: 05/21/2024] Open
Abstract
Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.
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Affiliation(s)
- Yue Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lei Tao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiahao Qiu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinyu Yang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Yu Zhang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
- School of Medicine, Tibet University, Lhasa, 850000, China
| | - Xinyu Tian
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinqi Guan
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaobo Cen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yinglan Zhao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Filho FDSA, Santiago LH, Fernandes ACN, Korn GP, Pontes PADL, Camponês do Brasil ODO. Preliminary Correlation of the Immunoexpression of Cathepsin B and E-Cadherin Proteins in Vocal Fold Leukoplakia. J Voice 2024; 38:760-767. [PMID: 34663533 DOI: 10.1016/j.jvoice.2021.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 08/09/2021] [Accepted: 08/11/2021] [Indexed: 11/17/2022]
Abstract
OBJECTIVES Early identification of vocal fold leukoplakia (VFL), which has a risk of progressing to malignant transformation, remains a controversial topic. The identification of biological markers for diagnosing these lesions would lead to a more effective treatment. We aimed to analyze the immunoexpression of cathepsin B and E-cadherin in VFL and correlate it with clinical and epidemiological data and disease prognosis. METHODS Thirty-two patients with VFL treated with microsurgery were retrospectively evaluated. The patients were distributed according to the histological results into Group A (low grade) and Group B (high grade). The expression of markers was quantitatively determined as per their staining intensity and tissue distribution using ImageLab. The index of expression (IE) of each marker was correlated with tobacco and alcohol consumption, signs of laryngopharyngeal reflux, and local recurrence of the lesion. RESULTS The correlation between the IE of markers and variables within the two groups (A and B) demonstrated that patients in Group B with local recurrence had a higher IE of cathepsin B. When all patients (A + B) were included, the same analysis demonstrated that the IE of cathepsin B was higher among smokers and patients who did not show signs of reflux and that the IE of E-cadherin was higher only in patients with recurrence. CONCLUSION Patients with moderate to severe dysplasia and carcinoma in situ who smoked as well as had a high IE of cathepsin B were more prone to local recurrence. Regardless of the type of histological lesion, patients with signs of laryngopharyngeal reflux had a lower IE of cathepsin B. The IE of E-cadherin was higher among patients with VFL who relapsed after initial treatment.
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Affiliation(s)
- Francisco de Souza Amorim Filho
- Department of Otolaryngology, Head and Neck Surgery of the Federal University of São Paulo, Paulista School of Medicine, São Paulo, Brazil
| | | | - Ana Carolina Nascimento Fernandes
- Laboratório de Ensino e Pesquisa em Otorrinolaringologia, Faculdade de Medicina, Universidade de Brasília, Campus Universitário Darcy Ribeiro, Asa Norte, Brasília/DF, Brazil.
| | - Gustavo Polacow Korn
- Department of Otolaryngology and Head, Neck Surgery of the Federal University of São Paulo, Paulista School of Medicine, São Paulo, Brazil
| | - Paulo Augusto de Lima Pontes
- Department of Otolaryngology, Head and Neck Surgery of the Federal University of São Paulo, Paulista Medical School, São Paulo, Brazil
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Poh AR, Ernst M. Functional roles of SRC signaling in pancreatic cancer: Recent insights provide novel therapeutic opportunities. Oncogene 2023:10.1038/s41388-023-02701-x. [PMID: 37120696 DOI: 10.1038/s41388-023-02701-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 04/19/2023] [Indexed: 05/01/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a 5-year survival rate of <10%. Aberrant activation or elevated expression of the tyrosine kinase c-SRC (SRC) is frequently observed in PDAC and is associated with a poor prognosis. Preclinical studies have revealed a multifaceted role for SRC activation in PDAC, including promoting chronic inflammation, tumor cell proliferation and survival, cancer cell stemness, desmoplasia, hypoxia, angiogenesis, invasion, metastasis, and drug resistance. Strategies to inhibit SRC signaling include suppressing its catalytic activity, inhibiting protein stability, or by interfering with signaling components of the SRC signaling pathway including suppressing protein interactions of SRC. In this review, we discuss the molecular and immunological mechanisms by which aberrant SRC activity promotes PDAC tumorigenesis. We also provide a comprehensive update of SRC inhibitors in the clinic, and discuss the clinical challenges associated with targeting SRC in pancreatic cancer.
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Affiliation(s)
- Ashleigh R Poh
- Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Melbourne, VIC, 3084, Australia.
| | - Matthias Ernst
- Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Melbourne, VIC, 3084, Australia.
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Shichi Y, Gomi F, Sasaki N, Nonaka K, Arai T, Ishiwata T. Epithelial and Mesenchymal Features of Pancreatic Ductal Adenocarcinoma Cell Lines in Two- and Three-Dimensional Cultures. J Pers Med 2022; 12:jpm12050746. [PMID: 35629168 PMCID: PMC9146102 DOI: 10.3390/jpm12050746] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/01/2022] [Accepted: 05/02/2022] [Indexed: 02/01/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an intractable cancer that is difficult to diagnose early, and there is no cure other than surgery. PDAC is classified as an adenocarcinoma that has limited effective anticancer drug and molecular-targeted therapies compared to adenocarcinoma found in other organs. A large number of cancer cell lines have been established from patients with PDAC that have different genetic abnormalities, including four driver genes; however, little is known about the differences in biological behaviors among these cell lines. Recent studies have shown that PDAC cell lines can be divided into epithelial and mesenchymal cell lines. In 3D cultures, morphological and functional differences between epithelial and mesenchymal PDAC cell lines were observed as well as the drug effects of different anticancer drugs. These effects included gemcitabine causing an increased growth inhibition of epithelial PDAC cells, while nab-paclitaxel caused greater mesenchymal PDAC cell inhibition. Thus, examining the characteristics of epithelial or mesenchymal PDAC cells with stromal cells using a 3D co-culture may lead to the development of new anticancer drugs.
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Affiliation(s)
- Yuuki Shichi
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan; (Y.S.); (F.G.); (K.N.)
| | - Fujiya Gomi
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan; (Y.S.); (F.G.); (K.N.)
| | - Norihiko Sasaki
- Research Team for Geriatric Medicine (Vascular Medicine), Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan;
| | - Keisuke Nonaka
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan; (Y.S.); (F.G.); (K.N.)
| | - Tomio Arai
- Department of Pathology, Tokyo Metropolitan Hospital and Institute of Gerontology, Tokyo 173-0015, Japan;
| | - Toshiyuki Ishiwata
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan; (Y.S.); (F.G.); (K.N.)
- Correspondence: ; Tel.: +81-3-3964-1141 (ext. 4414)
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Porcine pancreatic ductal epithelial cells transformed with KRAS G12D and SV40T are tumorigenic. Sci Rep 2021; 11:13436. [PMID: 34183736 PMCID: PMC8238942 DOI: 10.1038/s41598-021-92852-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 06/16/2021] [Indexed: 12/27/2022] Open
Abstract
We describe our initial studies in the development of an orthotopic, genetically defined, large animal model of pancreatic cancer. Primary pancreatic epithelial cells were isolated from pancreatic duct of domestic pigs. A transformed cell line was generated from these primary cells with oncogenic KRAS and SV40T. The transformed cell lines outperformed the primary and SV40T immortalized cells in terms of proliferation, population doubling time, soft agar growth, transwell migration and invasion. The transformed cell line grew tumors when injected subcutaneously in nude mice, forming glandular structures and staining for epithelial markers. Future work will include implantation studies of these tumorigenic porcine pancreatic cell lines into the pancreas of allogeneic and autologous pigs. The resultant large animal model of pancreatic cancer could be utilized for preclinical research on diagnostic, interventional, and therapeutic technologies.
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Kocsmár É, Lotz G, Kiss A, Hoerner M, Petrova E, Freudenberg N, Csanádi Á, Kulemann B, Werner M, Bronsert P, Wellner UF. Prognostic impact of tumor budding and EMT in periampullary adenocarcinoma: a quantitative approach. J Cancer 2020; 11:6474-6483. [PMID: 33046968 PMCID: PMC7545681 DOI: 10.7150/jca.46093] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 08/02/2020] [Indexed: 12/18/2022] Open
Abstract
The presence of invasive cell clusters known as tumor budding and the closely related epithelial mesenchymal transition (EMT) have a prognostic impact on cancer patients' overall survival. Interestingly, data quantitatively analyzing and correlating the amount of tumor buds and patient overall survival as well as the impact of expression of epithelial phenotype markers are missing. Periampullary carcinoma samples of 171 patients were immunohistochemically stained for E-Cadherin (ECad). Tumor cell clusters (TCC, defined from one to 50 cells) were manually quantified comprising tumor cell number and subcellular localization of ECad expression (membranous, cytoplasmic or mixed). Data analyses were performed using elastic net feature selection. Hereby, five distinct intervals of TCC sizes and corresponding fractions of cells with distinct ECad expression were identified. Prognostic features of the defined budding categories were entered into a subsequent Cox regression model together with standard clinicopathological parameters and, based on the model prediction, cases were categorized into "low and high budding" grades. Overall median TCC size was 16 cells (range: 2-36 cells). The median number of TCCs per tumor was 42 (range: 3-283). Elastic net feature selection identified TCCs of 6-10 and 31-35 cells as prognostically most relevant negative and positive features, respectively. Regarding ECad expression, cytoplasmic ECad expression in TCCs of 11-15 as well as of 26-30 cells revealed prognostic relevance. Combining TCC numbers and ECad expression, budding grade qualified as independent prognostic factor for patient overall survival (p<0.001) in a multivariable clinicopathologic Cox model. Applying an advanced modelling by machine learning on a cohort of periampullary cancers, we show that not the smallest TCCs (1-5 cells) but tumor cell nests containing 6-10 cells display the strongest negative prognostic relevance. Moreover, we demonstrate that larger TCCs might have a strong positive prognostic impact in periampullary adenocarcinomas, contributing to establishing an advanced grading system.
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Affiliation(s)
- Éva Kocsmár
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Gábor Lotz
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - András Kiss
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Markus Hoerner
- Institute of Surgical Pathology, University Medical Center, Freiburg, Germany
| | | | - Nikolaus Freudenberg
- Institute of Surgical Pathology, University Medical Center, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Germany
| | - Ágnes Csanádi
- Institute of Surgical Pathology, University Medical Center, Freiburg, Germany
| | - Birte Kulemann
- Faculty of Medicine, University of Freiburg, Germany
- Department of Surgery, University Medical Center, Freiburg, Germany
| | - Martin Werner
- Institute of Surgical Pathology, University Medical Center, Freiburg, Germany
- Tumorbank Comprehensive Cancer Center Freiburg, Medical Center - University of Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Germany
- German Consortium for Translational Cancer Research, Freiburg, Germany
| | - Peter Bronsert
- Institute of Surgical Pathology, University Medical Center, Freiburg, Germany
- Tumorbank Comprehensive Cancer Center Freiburg, Medical Center - University of Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Germany
- German Consortium for Translational Cancer Research, Freiburg, Germany
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Liu X, Xu J, Zhang B, Liu J, Liang C, Meng Q, Hua J, Yu X, Shi S. The reciprocal regulation between host tissue and immune cells in pancreatic ductal adenocarcinoma: new insights and therapeutic implications. Mol Cancer 2019; 18:184. [PMID: 31831007 PMCID: PMC6909567 DOI: 10.1186/s12943-019-1117-9] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 12/03/2019] [Indexed: 02/08/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death and is one of the most difficult-to-treat cancers. Surgical resection and adjuvant therapy have limited effects on the overall survival of PDAC patients. PDAC exhibits an immunosuppressive microenvironment, the immune response predicts survival, and activation of immune system has the potential to produce an efficacious PDAC therapy. However, chimeric antigen receptor T (CAR-T) cell immunotherapy and immune checkpoint blockade (ICB), which have produced unprecedented clinical benefits in a variety of different cancers, produce promising results in only some highly selected patients with PDAC. This lack of efficacy may be because existing immunotherapies mainly target the interactions between cancer cells and immune cells. However, PDAC is characterized by an abundant tumor stroma that includes a heterogeneous mixture of immune cells, fibroblasts, endothelial cells, neurons and some molecular events. Immune cells engage in extensive and dynamic crosstalk with stromal components in the tumor tissue in addition to tumor cells, which subsequently impacts tumor suppression or promotion to a large extent. Therefore, exploration of the interactions between the stroma and immune cells may offer new therapeutic opportunities for PDAC. In this review, we discuss how infiltrating immune cells influence PDAC development and explore the contributions of complex components to the immune landscape of tumor tissue. The roles of stromal constituents in immune modulation are emphasized. We also predict potential therapeutic strategies to target signals in the immune network in the abundant stromal microenvironment of PDAC.
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Affiliation(s)
- Xiaomeng Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
| | - Jiang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
| | - Chen Liang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
| | - Qingcai Meng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
| | - Jie Hua
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
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Mok L, Kim Y, Lee S, Choi S, Lee S, Jang JY, Park T. HisCoM-PAGE: Hierarchical Structural Component Models for Pathway Analysis of Gene Expression Data. Genes (Basel) 2019; 10:E931. [PMID: 31739607 PMCID: PMC6896173 DOI: 10.3390/genes10110931] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 11/06/2019] [Accepted: 11/07/2019] [Indexed: 01/10/2023] Open
Abstract
Although there have been several analyses for identifying cancer-associated pathways, based on gene expression data, most of these are based on single pathway analyses, and thus do not consider correlations between pathways. In this paper, we propose a hierarchical structural component model for pathway analysis of gene expression data (HisCoM-PAGE), which accounts for the hierarchical structure of genes and pathways, as well as the correlations among pathways. Specifically, HisCoM-PAGE focuses on the survival phenotype and identifies its associated pathways. Moreover, its application to real biological data analysis of pancreatic cancer data demonstrated that HisCoM-PAGE could successfully identify pathways associated with pancreatic cancer prognosis. Simulation studies comparing the performance of HisCoM-PAGE with other competing methods such as Gene Set Enrichment Analysis (GSEA), Global Test, and Wald-type Test showed HisCoM-PAGE to have the highest power to detect causal pathways in most simulation scenarios.
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Affiliation(s)
- Lydia Mok
- Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 08826, Korea
| | - Yongkang Kim
- Department of Statistics, Seoul National University, Seoul 08826, Korea
| | - Sungyoung Lee
- Center for Precision Medicine, Seoul National University Hospital, Seoul 03080, Korea
| | - Sungkyoung Choi
- Department of Applied Mathematics, Hanyang University (ERICA), Ansan 15588, Korea
| | - Seungyeoun Lee
- Department of Mathematics and Statistics, Sejong University, Seoul 05006, Korea
| | - Jin-Young Jang
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Taesung Park
- Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 08826, Korea
- Department of Statistics, Seoul National University, Seoul 08826, Korea
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Abstract
Although common evolutionary principles drive the growth of cancer cells regardless of the tissue of origin, the microenvironment in which tumours arise substantially differs across various organ sites. Recent studies have established that, in addition to cell-intrinsic effects, tumour growth regulation also depends on local cues driven by tissue environmental factors. In this Review, we discuss how tissue-specific determinants might influence tumour development and argue that unravelling the tissue-specific contribution to tumour immunity should help the development of precise immunotherapeutic strategies for patients with cancer.
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Affiliation(s)
- Hélène Salmon
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Precision Immunology Institute and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- INSERM U932, Institut Curie, Paris, France.
| | | | - Sacha Gnjatic
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Precision Immunology Institute and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Miriam Merad
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Precision Immunology Institute and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Fouani L, Kovacevic Z, Richardson DR. Targeting Oncogenic Nuclear Factor Kappa B Signaling with Redox-Active Agents for Cancer Treatment. Antioxid Redox Signal 2019; 30:1096-1123. [PMID: 29161883 DOI: 10.1089/ars.2017.7387] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
SIGNIFICANCE Nuclear factor kappa B (NF-κB) signaling is essential under physiologically relevant conditions. However, aberrant activation of this pathway plays a pertinent role in tumorigenesis and contributes to resistance. Recent Advances: The importance of the NF-κB pathway means that its targeting must be specific to avoid side effects. For many currently used therapeutics and those under development, the ability to generate reactive oxygen species (ROS) is a promising strategy. CRITICAL ISSUES As cancer cells exhibit greater ROS levels than their normal counterparts, they are more sensitive to additional ROS, which may be a potential therapeutic niche. It is known that ROS are involved in (i) the activation of NF-κB signaling, when in sublethal amounts; and (ii) high levels induce cytotoxicity resulting in apoptosis. Indeed, ROS-induced cytotoxicity is valuable for its capabilities in killing cancer cells, but establishing the potency of ROS for effective inhibition of NF-κB signaling is necessary. Indeed, some cancer treatments, currently used, activate NF-κB and may stimulate oncogenesis and confer resistance. FUTURE DIRECTIONS Thus, combinatorial approaches using ROS-generating agents alongside conventional therapeutics may prove an effective tactic to reduce NF-κB activity to kill cancer cells. One strategy is the use of thiosemicarbazones, which form redox-active metal complexes that generate high ROS levels to deliver potent antitumor activity. These agents also upregulate the metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), which functions as an NF-κB signaling inhibitor. It is proposed that targeting NF-κB signaling may proffer a new therapeutic niche to improve the efficacy of anticancer regimens.
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Affiliation(s)
- Leyla Fouani
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, Australia
| | - Zaklina Kovacevic
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, Australia
| | - Des R Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, Australia
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12
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Dosch AR, Dai X, Gaidarski Iii AA, Shi C, Castellanos JA, VanSaun MN, Merchant NB, Nagathihalli NS. Src kinase inhibition restores E-cadherin expression in dasatinib-sensitive pancreatic cancer cells. Oncotarget 2019; 10:1056-1069. [PMID: 30800218 PMCID: PMC6383685 DOI: 10.18632/oncotarget.26621] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 01/02/2019] [Indexed: 01/06/2023] Open
Abstract
The Src family of non-receptor tyrosine kinases are frequently activated in pancreatic ductal adenocarcinoma (PDAC), contributing to disease progression through downregulation of E-cadherin and induction of epithelial-to-mesenchymal transition (EMT). The purpose of this study was to examine the efficacy of Src kinase inhibition in restoring E-cadherin levels in PDAC. Immunohistochemical analysis of human PDAC samples showed Src activation is inversely correlated with E-cadherin levels. Protein and mRNA levels of E-cadherin, the gene expression of its various transcriptional repressors (Zeb1, Snail, Slug, LEF-1, TWIST), and changes in sub-cellular localization of E-cadherin/β-catenin in PDAC cells were characterized in response to treatment with the Src inhibitor, dasatinib (DST). DST repressed Slug mRNA expression, promoted E-cadherin transcription, and increased total and membranous E-cadherin/β-catenin levels in drug-sensitive PDAC cells (BxPC3 and SW1990), however no change was observed in drug-resistant PANC1 cells. BxPC3, PANC1, and MiaPaCa-2 flank tumor xenografts were treated with DST to examine changes in E-cadherin levels in vivo. Although DST inhibited Src phosphorylation in all xenograft models, E-cadherin levels were only restored in BxPC3 xenograft tumors. These results suggest that Src kinase inhibition reverses EMT in drug-sensitive PDAC cells through Slug-mediated repression of E-cadherin and identifies E-cadherin as potential biomarker for determining response to DST treatment.
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Affiliation(s)
- Austin R Dosch
- Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Xizi Dai
- Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Alexander A Gaidarski Iii
- Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Chanjuan Shi
- Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Jason A Castellanos
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Michael N VanSaun
- Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Nipun B Merchant
- Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Nagaraj S Nagathihalli
- Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
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13
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Abstract
OBJECTIVES Epithelial-mesenchymal transition (EMT) plays an important role in the progression, metastasis, and chemoresistance of pancreatic duct adenocarcinoma (PDAC); however, the expression of EMT markers and their clinical significance in PDAC patients who received neoadjuvant therapy (NAT) are unclear. METHODS We examined the expression of EMT markers, including Zeb-1 (zinc finger E-box-binding homeobox 1), E-cadherin, and vimentin by immunohistochemistry in 120 PDAC patients who received NAT and pancreatectomy from 1999 to 2007. The results were correlated with clinicopathologic parameters and survival. RESULTS Among 120 cases, 45 (37.5%) and 14 (11.7%) were positive for Zeb-1 and vimentin, respectively, and 25 (20.8%) were E-cadherin-low. The median overall survival and disease-free survival were 35.3 (standard deviation [SD], 2.8) and 15.9 (SD, 3.6) months, respectively, in vimentin-negative group compared with 16.1 (SD, 1.1) (P = 0.03) and 7.0 (SD, 1.1) months (P = 0.02) in the vimentin-positive group. In multivariate analysis, vimentin expression was an independent predictor of shorter disease-free survival (hazard ratio, 2.50; 95% confidence interval, 1.31-4.78; P = 0.016) and overall survival (hazard ratio, 2.55; 95% confidence interval, 1.33-4.89; P = 0.01). CONCLUSIONS Epithelial-mesenchymal transition markers are frequently expressed in treated PDAC. Vimentin expression is a prognostic biomarker for survival in PDAC patients who received NAT.
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14
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Zhu S, Deng S, He C, Liu M, Chen H, Zeng Z, Zhong J, Ye Z, Deng S, Wu H, Wang C, Zhao G. Reciprocal loop of hypoxia-inducible factor-1α (HIF-1α) and metastasis-associated protein 2 (MTA2) contributes to the progression of pancreatic carcinoma by suppressing E-cadherin transcription. J Pathol 2018; 245:349-360. [PMID: 29708271 DOI: 10.1002/path.5089] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 03/17/2018] [Accepted: 04/20/2018] [Indexed: 12/15/2022]
Abstract
Metastasis-associated protein 2 (MTA2) is overexpressed in certain malignancies, and plays important roles in tumour metastasis and progression. The present study highlights the function of MTA2 in pancreatic carcinoma through its role as a deacetylator of hypoxia-inducible factor-1α (HIF-1α) and a cotranscriptional factor for E-cadherin expression. We found that overexpression of MTA2 promoted, and knockdown of MTA2 inhibited, the invasion and proliferation of pancreatic carcinoma cells both in vitro and in xenograft models in vivo. We also found that MTA2 is transcriptionally upregulated by HIF-1α through a hypoxia response element (HRE) of the MTA2 promoter in response to hypoxia. Reciprocally, MTA2 deacetylates HIF-1α and enhances its stability through interacting with histone deacetylase 1 (HDAC1). Consequently, HIF-1α recruits MTA2 and HDAC1 to the HRE of the E-cadherin promoter, by which E-cadherin transcription is repressed. In agreement with these experimental results, MTA2 is positively associated with HIF-1α, but inversely correlated with E-cadherin, in pancreatic carcinoma samples. Moreover, data from The Cancer Genome Atlas on 172 pancreatic carcinomas indicate an association between high expression of MTA2 and short overall survival. Taken together, our study identifies MTA2 as a critical hub and potential therapeutic target to inhibit the progression and metastasis of pancreatic carcinoma. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Shuai Zhu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Shijiang Deng
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Chi He
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Mingliang Liu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Hengyu Chen
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Zhu Zeng
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Jianxin Zhong
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Zeng Ye
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Shichang Deng
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Heshui Wu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Chunyou Wang
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Gang Zhao
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
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15
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Di Domenico M, Giordano A. Signal transduction growth factors: the effective governance of transcription and cellular adhesion in cancer invasion. Oncotarget 2018; 8:36869-36884. [PMID: 28415812 PMCID: PMC5482705 DOI: 10.18632/oncotarget.16300] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 03/01/2017] [Indexed: 12/15/2022] Open
Abstract
Giulio Bizzozero classified the tissues concerning their capacity to self-renew during the adult life in labile, stable and permanent tissues. In 1940 Viktor Hamburger and Rita Levi Montalcini exposed the possibility to induce the growth of permanent cells thanks to a specific ligand Nerve Growth Factor (NGF). Stanley Cohen purified a protein the Epidermal Growth Factor (EGF), able to induce epidermis proliferation and to elicit precocious eye disclosure and teeth eruption, establishing the “inverse” relationships between the proliferation and differentiation. These two biological effects induced by EGF were according to EGFR signaling is involved in a large array of cellular functions such as proliferation, survival, adhesion, migration and differentiation. This review is focused on the key role of growth factors signaling and their downstream effectors in physiological and in pathological phenomena, the authors highlight the governance of Growth factors during the EMT in cancer invasion.
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Affiliation(s)
- Marina Di Domenico
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "Luigi Vanvitelli", Italy.,IRCCS Institute of Women's Health Malzoni Clinic, Avellino, Italy.,Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA, USA
| | - Antonio Giordano
- Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.,Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA, USA
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16
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Chen CN, Chen YT, Yang TL. Application of three-dimensional collagen scaffolds to recapitulate and monitor the dynamics of epithelial-mesenchymal transition during tumor satellite formation of head and neck cancer. Biomaterials 2018; 154:134-146. [DOI: 10.1016/j.biomaterials.2017.08.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2017] [Revised: 08/10/2017] [Accepted: 08/11/2017] [Indexed: 12/14/2022]
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17
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Ito S, Okuda S, Abe M, Fujimoto M, Onuki T, Nishimura T, Takeichi M. Induced cortical tension restores functional junctions in adhesion-defective carcinoma cells. Nat Commun 2017; 8:1834. [PMID: 29184140 PMCID: PMC5705652 DOI: 10.1038/s41467-017-01945-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 10/27/2017] [Indexed: 11/08/2022] Open
Abstract
Normal epithelial cells are stably connected to each other via the apical junctional complex (AJC). AJCs, however, tend to be disrupted during tumor progression, and this process is implicated in cancer dissemination. Here, using colon carcinoma cells that fail to form AJCs, we investigated molecular defects behind this failure through a search for chemical compounds that could restore AJCs, and found that microtubule-polymerization inhibitors (MTIs) were effective. MTIs activated GEF-H1/RhoA signaling, causing actomyosin contraction at the apical cortex. This contraction transmitted force to the cadherin-catenin complex, resulting in a mechanosensitive recruitment of vinculin to cell junctions. This process, in turn, recruited PDZ-RhoGEF to the junctions, leading to the RhoA/ROCK/LIM kinase/cofilin-dependent stabilization of the junctions. RhoGAP depletion mimicked these MTI-mediated processes. Cells that normally organize AJCs did not show such MTI/RhoA sensitivity. Thus, advanced carcinoma cells require elevated RhoA activity for establishing robust junctions, which triggers tension-sensitive reorganization of actin/adhesion regulators.
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Affiliation(s)
- Shoko Ito
- Laboratory for Cell Adhesion and Tissue Patterning, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Satoru Okuda
- Laboratoty for In Vitro Histogenesis, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Masako Abe
- Seed Compounds Exploratory Unit for Drug Discovery Platform, Drug Discovery Platforms Cooperation Division, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, 351-0198, Japan
| | - Mari Fujimoto
- Seed Compounds Exploratory Unit for Drug Discovery Platform, Drug Discovery Platforms Cooperation Division, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, 351-0198, Japan
| | - Tetsuo Onuki
- Seed Compounds Exploratory Unit for Drug Discovery Platform, Drug Discovery Platforms Cooperation Division, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, 351-0198, Japan
| | - Tamako Nishimura
- Laboratory for Cell Adhesion and Tissue Patterning, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan
- Nara Institute of Science and Technology, Ikoma, 630-0192, Japan
| | - Masatoshi Takeichi
- Laboratory for Cell Adhesion and Tissue Patterning, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
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18
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Chen CN, Chen YT, Yang TL. The data of establishing a three-dimensional culture system for in vitro recapitulation and mechanism exploration of tumor satellite formation during cancer cell transition. Data Brief 2017; 15:545-561. [PMID: 29071292 PMCID: PMC5651497 DOI: 10.1016/j.dib.2017.09.053] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 09/20/2017] [Accepted: 09/22/2017] [Indexed: 01/17/2023] Open
Abstract
Tumor satellite formation is an indicator of cancer invasiveness and correlates with recurrence, metastasis, and poorer prognosis. By analyzing pathological specimens, tumor satellites formed at the tumor-host interface reflect the phenomena of epithelial-mesenchymal transition. It is impossible to reveal the dynamic processes and the decisive factors of tumor satellite formation using clinicopathological approaches alone. Therefore, establishment of an in vitro system to monitor the phenomena is important to explicitly elucidate underlying mechanisms. In this study, we explored the feasibility of creating an in vitro three-dimensional collagen culture system to recapitulate the process of tumor satellite formation. This data presented here are referred to the research article (Chen et al., 2017) [1]. Using this model, the dynamic process of tumor satellite formation could be recapitulated in different types of human cancer cells. Induced by calcium deprivation, the treated cells increased the incidence and migratory distance of tumor satellites. E-cadherin internalization and invadopodia formation were enhanced by calcium deprivation and were associated with cellular dynamic change during tumor satellite formation. The data confirmed the utility of this culture system to recapitulate dynamic cellular alteration and to explore the potential mechanisms of tumor satellite formation.
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Affiliation(s)
- Chun-Nan Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - You-Tzung Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan.,Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan
| | - Tsung-Lin Yang
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.,Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan
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19
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Brychta N, Drosch M, Driemel C, Fischer JC, Neves RP, Esposito I, Knoefel W, Möhlendick B, Hille C, Stresemann A, Krahn T, Kassack MU, Stoecklein NH, von Ahsen O. Isolation of circulating tumor cells from pancreatic cancer by automated filtration. Oncotarget 2017; 8:86143-86156. [PMID: 29156783 PMCID: PMC5689673 DOI: 10.18632/oncotarget.21026] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 08/07/2017] [Indexed: 01/05/2023] Open
Abstract
It is now widely recognized that the isolation of circulating tumor cells based on cell surface markers might be hindered by variability in their protein expression. Especially in pancreatic cancer, isolation based only on EpCAM expression has produced very diverse results. Methods that are independent of surface markers and therefore independent of phenotypical changes in the circulating cells might increase CTC recovery also in pancreatic cancer. We compared an EpCAM-dependent (IsoFlux) and a size-dependent (automated Siemens Healthineers filtration device) isolation method for the enrichment of pancreatic cancer CTCs. The recovery rate of the filtration based approach is dramatically superior to the EpCAM-dependent approach especially for cells with low EpCAM-expression (filtration: 52%, EpCAM-dependent: 1%). As storage and shipment of clinical samples is important for centralized analyses, we also evaluated the use of frozen diagnostic leukapheresis (DLA) as source for isolating CTCs and subsequent genetic analysis such as KRAS mutation detection analysis. Using frozen DLA samples of pancreatic cancer patients we detected CTCs in 42% of the samples by automated filtration.
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Affiliation(s)
- Nora Brychta
- Bayer AG, Biomarker Research, 13353 Berlin, Germany
| | - Michael Drosch
- Bayer AG, Biomarker Research, 13353 Berlin, Germany.,Current/Present address: JPT Peptide Technologies GmbH, 12489 Berlin, Germany
| | - Christiane Driemel
- Department of General, Visceral and Pediatric Surgery, Medical Faculty, University Hospital of the Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany
| | - Johannes C Fischer
- Department of General, Visceral and Pediatric Surgery, Medical Faculty, University Hospital of the Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany
| | - Rui P Neves
- Department of General, Visceral and Pediatric Surgery, Medical Faculty, University Hospital of the Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany
| | - Irene Esposito
- Institute of Pathology, Heinrich-Heine-University of Duesseldorf, 40225 Duesseldorf, Germany
| | - Wolfram Knoefel
- Department of General, Visceral and Pediatric Surgery, Medical Faculty, University Hospital of the Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany
| | - Birte Möhlendick
- Department of General, Visceral and Pediatric Surgery, Medical Faculty, University Hospital of the Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany
| | - Claudia Hille
- Bayer AG, Biomarker Research, 13353 Berlin, Germany.,Current/Present address: University Medical Center Hamburg-Eppendorf, Department of Tumor Biology, 20246 Hamburg, Germany
| | | | - Thomas Krahn
- Bayer AG, Biomarker Research, 13353 Berlin, Germany
| | - Matthias U Kassack
- Institute of Pharmaceutical & Medicinal Chemistry, University of Duesseldorf, 40225 Duesseldorf, Germany
| | - Nikolas H Stoecklein
- Department of General, Visceral and Pediatric Surgery, Medical Faculty, University Hospital of the Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany
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20
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Winship A, Menkhorst E, Van Sinderen M, Dimitriadis E. Interleukin 11: similar or opposite roles in female reproduction and reproductive cancer? Reprod Fertil Dev 2017; 28:395-405. [PMID: 25151993 DOI: 10.1071/rd14128] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Accepted: 07/03/2014] [Indexed: 12/12/2022] Open
Abstract
During placental development and carcinogenesis, cell invasion and migration are critical events in establishing a self-supporting vascular supply. Interleukin (IL)-11 is a pleiotropic cytokine that affects the invasive and migratory capabilities of trophoblast cells that form the placenta during pregnancy, as well as various malignant cell types. The endometrium is the site of embryo implantation during pregnancy; conversely, endometrial carcinoma is the most common gynaecological malignancy. Here, we review what is known about the role of IL-11 in trophoblast function and in gynaecological malignancies, focusing primarily on the context of the uterine environment.
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Affiliation(s)
- Amy Winship
- Embryo Implantation Laboratory, MIMR-PHI Institute, 27-31 Wright Street, Clayton, Vic. 3168, Australia
| | - Ellen Menkhorst
- Embryo Implantation Laboratory, MIMR-PHI Institute, 27-31 Wright Street, Clayton, Vic. 3168, Australia
| | - Michelle Van Sinderen
- Embryo Implantation Laboratory, MIMR-PHI Institute, 27-31 Wright Street, Clayton, Vic. 3168, Australia
| | - Evdokia Dimitriadis
- Embryo Implantation Laboratory, MIMR-PHI Institute, 27-31 Wright Street, Clayton, Vic. 3168, Australia
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21
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Li B, Huang C. Regulation of EMT by STAT3 in gastrointestinal cancer (Review). Int J Oncol 2017; 50:753-767. [PMID: 28098855 DOI: 10.3892/ijo.2017.3846] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 11/10/2016] [Indexed: 11/06/2022] Open
Abstract
Gastrointestinal (GI) cancer is characterized by its aggressiveness and tendency to metastasize at early stage. Epithelial-mesenchymal transition (EMT), commonly known as the preparing step of metastasis, may account for the aggressive phenotype of GI cancer cells. The process of EMT is finely orchestrated by multiple layers of regulators. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor constitutively activated in diverse malignancies. Recent studies have suggested an involvement of STAT3 in GI cancer EMT. In this review, we first take an insight into the oncogenic functions of STAT3 in GI cancer, and then summarize the possible mechanisms by which STAT3 regulates the EMT process. Through the extensive interactions with EMT-inducing transcription factors and non-coding RNAs, and crosstalk with other signaling pathways, STAT3 has been demonstrated to promote the mesenchymal and invasive phenotype of GI cancer, which provides rationales for specifically targeting STAT3 to prevent and reverse the progression of GI cancer.
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Affiliation(s)
- Bo Li
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Chen Huang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
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22
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Zhao T, Jiang W, Wang X, Wang H, Zheng C, Li Y, Sun Y, Huang C, Han ZB, Yang S, Jia Z, Xie K, Ren H, Hao J. ESE3 Inhibits Pancreatic Cancer Metastasis by Upregulating E-Cadherin. Cancer Res 2016; 77:874-885. [PMID: 27923832 DOI: 10.1158/0008-5472.can-16-2170] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 11/12/2016] [Accepted: 11/19/2016] [Indexed: 12/15/2022]
Abstract
The ETS family transcription factor ESE3 is a crucial element in differentiation and development programs for many epithelial tissues. Here we report its role as a tumor suppressor in pancreatic cancer. We observed drastically lower ESE3 expression in pancreatic ductal adenocarcinomas (PDAC) compared with adjacent normal pancreatic tissue. Reduced expression of ESE3 in PDAC correlated closely with an increase in lymph node metastasis and vessel invasion and a decrease in relapse-free and overall survival in patients. In functional experiments, downregulating the expression of ESE3 promoted PDAC cell motility and invasiveness along with metastasis in an orthotopic mouse model. Mechanistic studies in PDAC cell lines, the orthotopic mouse model, and human PDAC specimens demonstrated that ESE3 inhibited PDAC metastasis by directly upregulating E-cadherin expression at the level of its transcription. Collectively, our results establish ESE3 as a negative regulator of PDAC progression and metastasis by enforcing E-cadherin upregulation. Cancer Res; 77(4); 874-85. ©2016 AACR.
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Affiliation(s)
- Tiansuo Zhao
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, P.R. China.,Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Wenna Jiang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, P.R. China
| | - Xiuchao Wang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, P.R. China
| | - Hongwei Wang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, P.R. China
| | - Chen Zheng
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, P.R. China
| | - Yang Li
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, P.R. China
| | - Yan Sun
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, P.R. China
| | - Chongbiao Huang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, P.R. China
| | - Zhi-Bo Han
- Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, P.R. China
| | - Shengyu Yang
- Department of Tumor Biology and Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Zhiliang Jia
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Keping Xie
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - He Ren
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, P.R. China
| | - Jihui Hao
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, P.R. China.
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23
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Mitrović Ajtić O, Todorović S, Diklić M, Subotički T, Beleslin-Čokić B, Jovčić G, Čokić V. Proliferation and differentiation markers of colorectal adenocarcinomaand their correlation with clinicopathological factors. Turk J Med Sci 2016; 46:1168-76. [PMID: 27513421 DOI: 10.3906/sag-1412-85] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 11/07/2015] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND/AIM The purpose of this study was to investigate proliferation and differentiation markers in colorectal adenocarcinoma and their correlation with clinicopathological factors. MATERIALS AND METHODS Samples were collected from 38 patients with colorectal adenocarcinoma and 10 healthy controls. E-cadherin, carcinoembryonic antigen (mCEA), cyclin B1, vascular endothelial growth factor (VEGF), and erythropoietin (EPO) receptor (EPOR) were examined by immunohistochemistry; VEGF and EPO were examined by real-time PCR. RESULTS The tumor samples were mostly characterized by large dimension (pT3), moderate level of differentiation (G2), negative lymph node status (N0), and no metastasis. Cyclin B1 and VEGF gene and protein expressions were significantly higher in tumor tissues than in control tissues; E-cadherin expression was significantly decreased in tumor samples and in positive correlation with mCEA. EPO was almost undetectable in tumor tissues of colorectal adenocarcinoma. Significant positive correlation was detected between tumor size and cyclin B1, tumor grade, and lymph node status. CONCLUSION Decreased expression of EPO, high levels of VEGF and cyclin B1 expression, predominant moderate tumor differentiation, absence of metastasis, and negative lymph node status may suggest low level of aggressiveness, better prognosis, and longer patient survival.
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Affiliation(s)
| | | | - Miloš Diklić
- Institute for Medical Research, University of Belgrade, Belgrade, Serbia
| | - Tijana Subotički
- Institute for Medical Research, University of Belgrade, Belgrade, Serbia
| | - Bojana Beleslin-Čokić
- Clinic of Endocrinology, Diabetes and Diseases of Metabolism, Clinical Center of Serbia, Belgrade, Serbia
| | - Gordana Jovčić
- Institute for Medical Research, University of Belgrade, Belgrade, Serbia
| | - Vladan Čokić
- Institute for Medical Research, University of Belgrade, Belgrade, Serbia
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Mathew S, Abdel-Hafiz H, Raza A, Fatima K, Qadri I. Host nucleotide polymorphism in hepatitis B virus-associated hepatocellular carcinoma. World J Hepatol 2016; 8:485-498. [PMID: 27057306 PMCID: PMC4820640 DOI: 10.4254/wjh.v8.i10.485] [Citation(s) in RCA: 14] [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: 09/12/2015] [Revised: 12/04/2015] [Accepted: 03/07/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is etiologically linked with hepatitis B virus (HBV) and is the leading cause of death amongst 80% of HBV patients. Among HBV affected patients, genetic factors are also involved in modifying the risk factors of HCC. However, the genetic factors that regulate progression to HCC still remain to be determined. In this review, we discuss several single nucleotide polymorphisms (SNPs) which were reportedly associated with increased or reduced risk of HCC occurrence in patients with chronic HBV infection such as cyclooxygenase (COX)-2 expression specifically at COX-2 -1195G/A in Chinese, Turkish and Egyptian populations, tumor necrosis factor α and the three most commonly studied SNPs: PAT-/+, Lys939Gln (A33512C, rs2228001) and Ala499Val (C21151T, rs2228000). In genome-wide association studies, strong associations have also been found at loci 1p36.22, 11q22.3, 6p21 (rs1419881, rs3997872, rs7453920 and rs7768538), 8p12 (rs2275959 and rs37821974) and 22q11.21. The genes implicated in these studies include HLA-DQB2, HLA-DQA1, TCF19, HLA-C, UBE2L3, LTL, FDX1, MICA, UBE4B and PG. The SNPs found to be associated with the above-mentioned genes still require validation in association studies in order to be considered good prognostic candidates for HCC. Screening of these polymorphisms is very beneficial in clinical experiments to stratify the higher or lower risk for HCC and may help in designing effective and efficient HCC surveillance programs for chronic HBV-infected patients if further genetic vulnerabilities are detected.
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Affiliation(s)
- Shilu Mathew
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Hany Abdel-Hafiz
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Abbas Raza
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Kaneez Fatima
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Ishtiaq Qadri
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
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Wong J, Solomon NL, Hsueh CT. Neoadjuvant treatment for resectable pancreatic adenocarcinoma. World J Clin Oncol 2016; 7:1-8. [PMID: 26862486 PMCID: PMC4734931 DOI: 10.5306/wjco.v7.i1.1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 11/06/2015] [Accepted: 11/17/2015] [Indexed: 02/06/2023] Open
Abstract
Pancreatic adenocarcinoma is the fourth leading cause of cancer mortality in the United States in both men and women, with a 5-year survival rate of less than 5%. Surgical resection remains the only curative treatment, but most patients develop systemic recurrence within 2 years of surgery. Adjuvant treatment with chemotherapy or chemoradiotherapy has been shown to improve overall survival, but the delivery of treatment remains problematic with up to 50% of patients not receiving postoperative treatment. Neoadjuvant therapy can provide benefits of eradication of micrometastasis and improved delivery of intended treatment. We have reviewed the findings from completed neoadjuvant clinical trials, and discussed the ongoing studies. Combinational cytotoxic chemotherapy such as fluorouracil, leucovorin, irinotecan, and oxaliplatin and gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel, active in the metastatic setting, are being studied in the neoadjuvant setting. In addition, novel targeted agents such as inhibitor of immune checkpoint are incorporated with cytotoxic chemotherapy in early-phase clinical trial. Furthermore we have explored the utility of biomarkers which can personalize treatment and select patients for target-driven therapy to improve treatment outcome. The treatment of resectable pancreatic adenocarcinoma requires multidisciplinary approach and novel strategies including innovative trials to make progress.
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26
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Fink DM, Steele MM, Hollingsworth MA. The lymphatic system and pancreatic cancer. Cancer Lett 2015; 381:217-36. [PMID: 26742462 DOI: 10.1016/j.canlet.2015.11.048] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Revised: 11/16/2015] [Accepted: 11/30/2015] [Indexed: 02/06/2023]
Abstract
This review summarizes current knowledge of the biology, pathology and clinical understanding of lymphatic invasion and metastasis in pancreatic cancer. We discuss the clinical and biological consequences of lymphatic invasion and metastasis, including paraneoplastic effects on immune responses and consider the possible benefit of therapies to treat tumors that are localized to lymphatics. A review of current techniques and methods to study interactions between tumors and lymphatics is presented.
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Affiliation(s)
- Darci M Fink
- Eppley Institute, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA
| | - Maria M Steele
- Eppley Institute, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA
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27
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Stark AP, Chang HH, Jung X, Moro A, Hertzer K, Xu M, Schmidt A, Hines OJ, Eibl G. E-cadherin expression in obesity-associated, Kras-initiated pancreatic ductal adenocarcinoma in mice. Surgery 2015; 158:1564-72. [PMID: 26297056 DOI: 10.1016/j.surg.2015.07.023] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 07/06/2015] [Accepted: 07/10/2015] [Indexed: 12/24/2022]
Abstract
BACKGROUND The epithelial-mesenchymal transition (EMT) is critical in the development of invasive epithelial malignancies. EMT is accelerated by inflammation and results in decreased E-cadherin expression. Diet-induced obesity is an inflammatory state that accelerates pancreatic carcinogenesis; its effect on EMT and E-cadherin expression in the development of pancreatic ductal adenocarcinoma is unclear. METHODS Conditional Kras(G12D) mice were fed a control diet or a high-fat, high-calorie diet for 3 or 9 months (n = 10 each). Immunohistochemistry with anti-E-cadherin antibody was performed. E-cadherin expression was characterized by staining intensity, location, and proportion of positive cells. In vitro expression of E-cadherin and Slug in primary pancreatic intraepithelial neoplasia (PanIN) and cancer cells was determined by Western blot. RESULTS The HFCD led to increased weight gain in both 3- (15.8 vs 5.6 g, P < .001) and 9-month (19.8 vs 12.9 g, P = .007) mice. No differences in E-cadherin expression among various stages of preinvasive PanIN lesions were found--regardless of age or diet. In invasive cancer, E-cadherin expression was aberrant, with loss of membranous staining and prominent cytoplasmic staining, associated with strong, cytoplasmic expression of β-catenin. In vitro expression of E-cadherin was greatest in primary PanIN cells, accompanied by absent Slug expression. Cancer cell lines demonstrated significantly decreased E-cadherin expression in the presence of upregulated Slug. CONCLUSION Despite increased pancreatic inflammation and accelerated carcinogenesis, the high-fat, high-calorie diet did not induce changes in E-cadherin expression in PanIN lesions of all stages. Invasive lesions demonstrated aberrant cytoplasmic E-cadherin staining. Loss of normal membranous localization may reflect a functional loss of E-cadherin.
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MESH Headings
- Adenocarcinoma/genetics
- Adenocarcinoma/metabolism
- Adenocarcinoma/pathology
- Animals
- Cadherins/genetics
- Cadherins/metabolism
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology
- Cell Line, Tumor
- Cells, Cultured
- Diet, High-Fat/adverse effects
- Disease Models, Animal
- Energy Intake
- Epithelial-Mesenchymal Transition
- Gene Expression Regulation, Neoplastic/genetics
- Gene Expression Regulation, Neoplastic/physiology
- In Vitro Techniques
- Mice
- Mice, Mutant Strains
- Mutation/genetics
- Neoplasm Staging
- Obesity/complications
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Proto-Oncogene Proteins p21(ras)/genetics
- Proto-Oncogene Proteins p21(ras)/metabolism
- Snail Family Transcription Factors
- Transcription Factors/genetics
- Transcription Factors/metabolism
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Affiliation(s)
- Alexander P Stark
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Hui-Hua Chang
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Xiaoman Jung
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Aune Moro
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Kathleen Hertzer
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Mu Xu
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Andrea Schmidt
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - O Joe Hines
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA.
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Arfmann-Knübel S, Struck B, Genrich G, Helm O, Sipos B, Sebens S, Schäfer H. The Crosstalk between Nrf2 and TGF-β1 in the Epithelial-Mesenchymal Transition of Pancreatic Duct Epithelial Cells. PLoS One 2015. [PMID: 26226105 PMCID: PMC4520686 DOI: 10.1371/journal.pone.0132978] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Nrf2 and TGF-β1 both affect tumorigenesis in a dual fashion, either by preventing carcinogen induced carcinogenesis and suppressing tumor growth, respectively, or by conferring cytoprotection and invasiveness to tumor cells during malignant transformation. Given the involvement of Nrf2 and TGF-β1 in the adaptation of epithelial cells to persistent inflammatory stress, e.g. of the pancreatic duct epithelium during chronic pancreatitis, a crosstalk between Nrf2 and TGF-β1 can be envisaged. By using premalignant human pancreatic duct cells (HPDE) and the pancreatic ductal adenocarcinoma cell line Colo357, we could show that Nrf2 and TGF-β1 independently but additively conferred an invasive phenotype to HPDE cells, whereas acting synergistically in Colo357 cells. This was accompanied by differential regulation of EMT markers like vimentin, Slug, L1CAM and E-cadherin. Nrf2 activation suppressed E-cadherin expression through an as yet unidentified ARE related site in the E-cadherin promoter, attenuated TGF-β1 induced Smad2/3-activity and enhanced JNK-signaling. In Colo357 cells, TGF-β1 itself was capable of inducing Nrf2 whereas in HPDE cells TGF-β1 per-se did not affect Nrf2 activity, but enhanced Nrf2 induction by tBHQ. In Colo357, but not in HPDE cells, the effects of TGF-β1 on invasion were sensitive to Nrf2 knock-down. In both cell lines, E-cadherin re-expression inhibited the proinvasive effect of Nrf2. Thus, the increased invasion of both cell lines relates to the Nrf2-dependent downregulation of E-cadherin expression. In line, immunohistochemistry analysis of human pancreatic intraepithelial neoplasias in pancreatic tissues from chronic pancreatitis patients revealed strong Nrf2 activity already in premalignant epithelial duct cells, accompanied by partial loss of E-cadherin expression. Our findings indicate that Nrf2 and TGF-β1 both contribute to malignant transformation through distinct EMT related mechanisms accounting for an invasive phenotype. Provided a crosstalk between both pathways, Nrf2 and TGF-β1 mutually promote their tumorigenic potential, a condition manifesting already at an early stage during inflammation induced carcinogenesis of the pancreas.
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Affiliation(s)
- Sarah Arfmann-Knübel
- Laboratory of Molecular Gastroenterology, Dept. of Internal Medicine I, UKSH Campus Kiel, Arnold-Heller-Str. 3, Bldg. 6, 24105, Kiel, Germany
| | - Birte Struck
- Laboratory of Molecular Gastroenterology, Dept. of Internal Medicine I, UKSH Campus Kiel, Arnold-Heller-Str. 3, Bldg. 6, 24105, Kiel, Germany
| | - Geeske Genrich
- Group Inflammatory Carcinogenesis, Institute of Experimental Medicine, CAU Kiel, Arnold-Heller-Str. 3, Bldg. 17, 24105, Kiel, Germany
| | - Ole Helm
- Group Inflammatory Carcinogenesis, Institute of Experimental Medicine, CAU Kiel, Arnold-Heller-Str. 3, Bldg. 17, 24105, Kiel, Germany
| | - Bence Sipos
- Department of Pathology and Neuropathology, University Hospital Tübingen, Liebermeisterstraße 8, 72076, Tübingen, Germany
| | - Susanne Sebens
- Group Inflammatory Carcinogenesis, Institute of Experimental Medicine, CAU Kiel, Arnold-Heller-Str. 3, Bldg. 17, 24105, Kiel, Germany
| | - Heiner Schäfer
- Laboratory of Molecular Gastroenterology, Dept. of Internal Medicine I, UKSH Campus Kiel, Arnold-Heller-Str. 3, Bldg. 6, 24105, Kiel, Germany
- * E-mail:
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Izumi H, Hirabayashi K, Nakamura N, Nakagohri T. Nectin expression in pancreatic adenocarcinoma: nectin-3 is associated with a poor prognosis. Surg Today 2015; 45:487-94. [PMID: 25690753 PMCID: PMC4359290 DOI: 10.1007/s00595-015-1126-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 01/20/2015] [Indexed: 01/09/2023]
Abstract
Purpose Nectins are cell adhesion molecules that regulate the formation of adherens junctions and are linked with E-cadherin-based cell–cell adherens junctions. In pancreatic cancer, the expression of E-cadherin and nectins is considered to be related to metastasis, invasion and prognosis. Methods We evaluated the distribution of cells that were positive for nectin subtypes and E-cadherin using immunohistochemistry in specimens of human pancreatic adenocarcinoma, and correlated these results with the clinicopathological features and patient outcomes. Results The immunohistochemical distribution of nectin-1 and E-cadherin showed a good correlation (r = 0.523, p < 0.01). Tumors over 4 cm in diameter had more intense staining for nectin-4 than smaller tumors (p = 0.035). Nectin-2 expression correlated with a poorer histological grade (p = 0.04). The cases that showed diffuse nectin-3 expression had a better prognosis than those with negative expression (p = 0.018). Conclusion Our results showed that the expression of nectin-3 in pancreatic cancer can be a prognostic factor.
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Affiliation(s)
- Hideki Izumi
- Department of Surgery, Tokai University School of Medicine, Kanagawa, Japan
| | - Kenichi Hirabayashi
- Department of Pathology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193 Japan
| | - Naoya Nakamura
- Department of Pathology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193 Japan
| | - Toshio Nakagohri
- Department of Surgery, Tokai University School of Medicine, Kanagawa, Japan
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Regulatory Variants and Disease: The E-Cadherin -160C/A SNP as an Example. Mol Biol Int 2014; 2014:967565. [PMID: 25276428 PMCID: PMC4167656 DOI: 10.1155/2014/967565] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2014] [Revised: 08/23/2014] [Accepted: 08/25/2014] [Indexed: 01/04/2023] Open
Abstract
Single nucleotide polymorphisms (SNPs) occurring in noncoding sequences have largely been ignored in genome-wide association studies (GWAS). Yet, amounting evidence suggests that many noncoding SNPs especially those that are in the vicinity of protein coding genes play important roles in shaping chromatin structure and regulate gene expression and, as such, are implicated in a wide variety of diseases. One of such regulatory SNPs (rSNPs) is the E-cadherin (CDH1) promoter -160C/A SNP (rs16260) which is known to affect E-cadherin promoter transcription by displacing transcription factor binding and has been extensively scrutinized for its association with several diseases especially malignancies. Findings from studying this SNP highlight important clinical relevance of rSNPs and justify their inclusion in future GWAS to identify novel disease causing SNPs.
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31
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Tracey E, Watt H, Currow D, Young J, Armstrong B. Investigation of poorer bladder cancer survival in women in NSW, Australia: a data linkage study. BJU Int 2014; 113:437-48. [PMID: 24127730 DOI: 10.1111/bju.12496] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To investigate the associations of a range of personal and clinical variables with bladder cancer survival in men and women in NSW to see if we could explain why bladder cancer survival is consistently poorer in women than in men. PATIENTS AND METHODS All 6880 cases of bladder cancers diagnosed in NSW between 2000 and 2008 were linked to hospital separation data and to deaths. Separate Cox proportional hazards regression models of hazard of bladder cancer death were constructed for those who did or did not undergo cystectomy. RESULTS A total of 16% of patients with bladder cancer underwent cystectomy (16% of men and 15% of women). Women who underwent cystectomy were 26% more likely to die than men (hazard ratio [HR] 1.26, 95% confidence interval [CI] 1.00-1.59) after adjustment for age, stage, time from diagnosis to cystectomy, distance from treatment facility and country of birth. None of the above covariates had a material effect on the difference in hazard between women and men; however, when stratified by a history of cystitis, the adjusted hazard was 55% higher in women (HR 1.55, 95% CI 1.15-2.10) than in men with a history of cystitis while, in the absence of this history, there was no difference in the hazard between men and women (HR 0.99, 95% CI 0.57-1.70). This apparent modification of the effect of sex on bladder cancer outcome was not seen in patients treated only by resection: the adjusted HRs in women relative to men were 1.10 (95% CI 0.92-1.31) in those with a history of cystitis and 1.21 (95% CI 0.98-1.50) in those without. A history of haematuria did not modify appreciably the association of sex with bladder cancer outcome. CONCLUSION Women's poorer survival from bladder cancer compared with that of men remains unexplained; however, the possibility that some factor associated with a history of cystitis may contribute to or explain the poorer outcome in women merits further investigation.
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32
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Levine PH, Hoffman HJ, MacNeil A, Hashmi S, Yang SX, Hewitt S, Golen KLV, Swain SM. Prognostic Value of Lymphocyte Vascular Density and E-Cadherin in Inflammatory Breast Cancer. ACTA ACUST UNITED AC 2014. [DOI: 10.4236/jct.2014.514139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Guo S, Jing W, Hu X, Zhou X, Liu L, Zhu M, Yin F, Chen R, Zhao J, Guo Y. Decreased TIP30 expression predicts poor prognosis in pancreatic cancer patients. Int J Cancer 2013; 134:1369-78. [PMID: 24037692 DOI: 10.1002/ijc.28471] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Revised: 08/03/2013] [Accepted: 08/20/2013] [Indexed: 12/12/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is known for its aggressive growth, and is characterized by early tissue invasion and metastasis with poor prognosis. Identifying prognostic markers and delineating the underlying mechanisms that promote progression of PDAC are important for the treatment of pancreatic cancer. TIP30, a newly identified tumor suppressor, appears to be involved in multiple processes during tumor development and metastasis. Here, we investigated the expression of TIP30 in PDAC and its prognostic value in PDAC patients. We examined the expression of TIP30 by immunohistochemistry in tissue microarrays containing 106 surgically resected PDAC. Kaplan-Meier analysis and Cox proportional hazards regression modeling analysis showed that TIP30 expression independently predicted better survival in pancreatectomy patients (p < 0.01). Moreover, decreased TIP30 expression was associated with lymph node metastasis (p < 0.05) and loss of E-cadherin expression (r = 0.329, p < 0.01). Suppression of TIP30 resulted in upregulation of Snail and subsequent downregulation of E-cadherin in SW1990 cells containing high-level of endogenous TIP30. However, in the PANC-1 cells containing low level of endogenous TIP30, suppressing TIP30 caused upregulation of Slug instead of Snail, followed by upregulation of MMP9 rather than E-cadherin. Taken together, our work reveals that decreased TIP30 expression is able to enhance invasion and metastasis of pancreatic cancer cells through upregulation of the Snail family members and may serve as an independent predictor for poor outcomes in PDAC patients.
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Affiliation(s)
- Shiwei Guo
- International Joint Cancer Research Institute, The Second Military Medical University, Shanghai, People's Republic of China; Department of general surgery, Changhai Hospital, The Second Military Medical University, Shanghai, People's Republic of China
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Wörmann SM, Diakopoulos KN, Lesina M, Algül H. The immune network in pancreatic cancer development and progression. Oncogene 2013; 33:2956-67. [PMID: 23851493 DOI: 10.1038/onc.2013.257] [Citation(s) in RCA: 144] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 04/22/2013] [Accepted: 04/22/2013] [Indexed: 02/07/2023]
Abstract
The presence of stromal desmoplasia is a hallmark of spontaneous pancreatic ductal adenocarcinoma, forming a unique microenvironment that comprises many cell types. Only recently, the immune system has entered the pathophysiology of pancreatic ductal adenocarcinoma development. Tumor cells in the pancreas seem to dysbalance the immune system, thus facilitating spontaneous cancer development. This review will try to assemble all relevant data to demonstrate the implications of the immune network on spontaneous cancer development.
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Affiliation(s)
- S M Wörmann
- Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - K N Diakopoulos
- Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - M Lesina
- Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - H Algül
- Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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Sarkar P, Kumar S. Calcium sensing receptor modulation for cancer therapy. Asian Pac J Cancer Prev 2013; 13:3561-8. [PMID: 23098435 DOI: 10.7314/apjcp.2012.13.8.3561] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
The calcium sensing receptor (CaSR) is a member of the largest family of cell surface receptors, the G protein-coupled receptors involved in calcium homeostasis. The role of the CaSR in neoplasia appears to be homeostatic; loss of normal CaSR-induced response to extracellular calcium is observed in cancers of the colon and ovary, while increased release of PTHrP is observed in cancers of the breast, prostate and Leydig cells. Currently CaSR can be considered as a molecule that can either promote or prevent tumor growth depending on the type of cancer. Therefore, recognition of the multifaceted role of CaSR in gliomas and other malignant tumors in general is fundamental to elucidating the mechanisms of tumor progression and the development of novel therapeutic agents. Emphasis should be placed on development of drug-targeting methods to modulate CaSR activity in cancer cells.
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Affiliation(s)
- Puja Sarkar
- IGNOU-I2IT Centre of Excellence for Advanced Education and Research, Pune, Maharashtra, India
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Guo S, Xu J, Xue R, Liu Y, Yu H. Overexpression of AIB1 correlates inversely with E-cadherin expression in pancreatic adenocarcinoma and may promote lymph node metastasis. Int J Clin Oncol 2013; 19:319-24. [PMID: 23542947 DOI: 10.1007/s10147-013-0549-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2012] [Accepted: 03/09/2013] [Indexed: 10/27/2022]
Abstract
BACKGROUND It was reported that the nuclear receptor coactivator amplified in breast cancer1 (AIB1) could regulate cancer cell invasion and migration in a nuclear receptor signaling-independent manner. Meanwhile, the process of epithelial mesenchymal transition (EMT) is critical for tumor invasion and metastasis. The present study aimed to determine the role of AIB1 and EMT markers in human pancreatic adenocarcinoma. METHODS AIB1, ZO-1, E-cadherin, vimentin, and N-cadherin protein expression in 76 pancreatic adenocarcinomas were assessed using immunohistochemistry and analyzed for clinicopathological significance. RESULTS The frequency of AIB1 overexpression in pancreatic adenocarcinomas with lymph node metastasis is 68 % (19/28), which is significantly higher than in pancreatic adenocarcinomas without lymph node metastasis (42 %; 20/48). In addition, the frequency of low expression of E-cadherin in pancreatic carcinomas with lymph node metastasis (68 %; 19/28) was significantly higher than in tumors without lymph node metastasis (44 %; 21/48). Correlation analysis demonstrated that the overexpression of AIB1 was inversely correlated with low expression of E-cadherin in pancreatic adenocarcinomas. CONCLUSION Overexpression of AIB1 might promote invasion and metastasis of cancer cells and is associated with down-regulation of E-cadherin in pancreatic adenocarcinomas.
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Affiliation(s)
- Si Guo
- Clinical Laboratory, Henan Provincial People's Hospital, 7 Wei Wu Road, Zhengzhou, 450000, China
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Hu Z, Liu X, Tang Z, Zhou Y, Qiao L. Possible regulatory role of Snail in NF-κB-mediated changes in E-cadherin in gastric cancer. Oncol Rep 2013; 29:993-1000. [PMID: 23254865 DOI: 10.3892/or.2012.2200] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Accepted: 10/30/2012] [Indexed: 12/22/2022] Open
Abstract
In the present study, we aimed to investigate the involvement of Snail in NF-κB-mediated changes of E-cadherin in gastric cancer. A total of 189 human gastric cancer tissues, and 32 normal gastric mucosal tissues were used to determine the expression levels of NF-κB, E-cadherin and Snail by immunohistochemistry. The correlation between the expression levels and patient clinicopathological data was analyzed. Human gastric cancer cell line SGC7901 was treated with the NF-κB inhibitor PDTC, and the expression levels of E-cadherin and Snail were investigated by qPCR and western blot. NF-κB, E-cadherin and Snail were all detected in normal gastric mucosa and cancer tissues of various differentiation statuses. However, the expression patterns of each protein were different. Strong expression of E-cadherin was detected in normal gastric mucosa, whereas its expression gradually declined in gastric cancer tissues, with weak expression observed in poorly differentiated gastric cancer tissues. In contrast, weak NF-κB and Snail expressions were present in normal gastric mucosa, while their expression levels gradually increased in gastric cancer tissues, with the strongest expression detected in poorly differentiated gastric cancers. The expression of E-cadherin was inversely correlated with that of Snail and NF-κB in the tissues tested. Blockade of NF-κB using its inhibitor PDTC led to a time-dependent reduction in Snail but a time-dependent increase in E-cadherin in SGC7901 cells. These results suggest that in human gastric cancer, loss of E-cadherin may be mediated through NF-κB-induced Snail upregulation. Further studies may reveal whether targeting the NF-κB-Snail-E-cadherin axis could be a useful approach for combating gastric cancer.
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Affiliation(s)
- Zenan Hu
- First Clinical Medical School of Lanzhou University, Lanzhou 730000, PR China
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Kontos CK, Mavridis K, Talieri M, Scorilas A. Kallikrein-related peptidases (KLKs) in gastrointestinal cancer: mechanistic and clinical aspects. Thromb Haemost 2013; 110:450-7. [PMID: 23446315 DOI: 10.1160/th12-11-0791] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Accepted: 01/31/2013] [Indexed: 01/20/2023]
Abstract
The human tissue kallikrein (KLK1) and kallikrein-related peptidases (KLKs) are secreted serine proteases with diverse expression patterns and physiological roles in different systems, including the digestive system. The aberrant expression of KLKs in gastrointestinal malignancies as well as their implication in carcinogenesis including cell growth regulation, angiogenesis, invasion, and metastasis, has prompted scientists to investigate their potential as cancer biomarkers. Expression of distinct KLKs is associated with various clinic-pathological parameters of patients with gastric, colorectal, pancreatic, hepatic, and esophageal cancer. Moreover, several KLKs possess significant favourable or unfavourable prognostic value in these human malignancies. Identification of novel diagnostic, prognostic and predictive biomarkers will contribute utmost to clinical decision-making, since early diagnosis of gastrointestinal cancer and early detection of recurrence following surgery are critical for the effective treatment of patients and for a positive clinical outcome. The current review provides a brief overview of the functional role of KLKs in gastric, colorectal, pancreatic, hepatic, and esophageal cancer, and describes the current status of KLKs as potential tumour biomarkers in these human malignancies.
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Affiliation(s)
- C K Kontos
- Assoc. Professor Andreas Scorilas, Department of Biochemistry and Molecular Biology, University of Athens, Panepistimiopolis, Athens 15701, Greece, Tel.: +30 210 727 4306, Fax: +30 210 727 4158, E-mail:
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Pal M, Koul S, Koul HK. The transcription factor sterile alpha motif (SAM) pointed domain-containing ETS transcription factor (SPDEF) is required for E-cadherin expression in prostate cancer cells. J Biol Chem 2013; 288:12222-31. [PMID: 23449978 DOI: 10.1074/jbc.m112.434225] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Loss of E-cadherin is one of the key steps in tumor progression. Our previous studies demonstrate that SAM pointed domain-containing ETS transcription factor (SPDEF) inhibited prostate cancer metastasis in vitro and in vivo. In the present study, we evaluated the relationship between SPDEF and E-cadherin expression in an effort to better understand the mechanism of action of SPDEF in prostate tumor cell invasion and metastasis. The results presented here demonstrate a direct correlation between expression of E-cadherin and SPDEF in prostate cancer cells. Additional data demonstrate that modulation of E-cadherin and SPDEF had similar effects on cell migration/invasion. In addition, siRNA-mediated knockdown of E-cadherin was sufficient to block the effects of SPDEF on cell migration and invasion. We also show that stable forced expression of SPDEF results in increased expression of E-cadherin, whereas down-regulation of SPDEF decreased E-cadherin expression. In addition, we demonstrate that SPDEF expression is not regulated by E-cadherin. Moreover, our chromatin immunoprecipitation and luciferase reporter assay revealed that SPDEF occupies E-cadherin promoter site and acts as a direct transcriptional inducer of E-cadherin in prostate cancer cells. Taken together, to the best of our knowledge, these studies are the first demonstrating requirement of SPDEF for expression of E-cadherin, an essential epithelial cell junction protein. Given that loss of E-cadherin is a central tenant in tumor metastasis, the results of our studies, by providing a new mechanism for regulation of E-cadherin expression, could have far reaching impact.
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Affiliation(s)
- Mintu Pal
- Program in Urosciences, Division of Urology, Department of Surgery, School of Medicine, Aurora, Colorado 80045, USA
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Pancreatic cancer cells retain the epithelial-related phenotype and modify mitotic spindle microtubules after the administration of ukrain in vitro. Anticancer Drugs 2013; 23:935-46. [PMID: 22700003 DOI: 10.1097/cad.0b013e32835507bc] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The aim of this study is to characterize the phenotype of pancreatic ductal adenocarcinoma (PDAC) cells in relation to the expression of epithelial-to-mesenchymal transition (EMT) markers and determine whether ukrain, an anticancer drug based on the alkaloids extracted from greater celandine, modulates in vitro the malignant behavior of PDAC cells in order to extend our understanding of its therapeutic potential. Three cell lines (HPAF-II, HPAC, and PL45) were treated with ukrain (5, 10, and 20 μmol/l) for 48 h or left untreated (control). Cell proliferation was assessed by growth curves. Apoptosis was determined by Hoechst nuclear staining and by cytochrome c and caspase-8 expressions. The EMT markers E-cadherin, β-catenin, and vimentin, as well as actin and tubulin cytoskeletons, were analyzed by immunofluorescence. Interphase and mitotic microtubules as well as abnormal mitotic figures were studied by fluorescence microscopy after tubulin immunolabeling. Ukrain strongly suppressed cell proliferation and induced apoptosis possibly through an extrinsic pathway as cytochrome c immunoreactivity suggested that the integrity of the mitochondria was not affected. Tubulin expression indicated an antiproliferative effect of ukrain on the basis of alterations in mitotic spindle microtubule dynamics, leading to abnormal mitosis. Membranous E-cadherin/β-catenin immunoreactivity was similarly expressed in control-treated and ukrain-treated cells, although the drug upregulated E-cadherin in cell lysates. Our results suggest that ukrain exerts its chemotherapeutic action on PDAC cells targeting mitotic spindle microtubules, leading to abnormal mitosis and apoptosis, and favoring cell cohesiveness. The differentiated epithelial phenotype of HPAF-II, HPAC, and PL45 cell lines concomitant with a highly invasive potential suggests that further experiments will be necessary to definitively clarify the role of EMT in PDAC progression.
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Lay V, Yap J, Sonderegger S, Dimitriadis E. Interleukin 11 regulates endometrial cancer cell adhesion and migration via STAT3. Int J Oncol 2012; 41:759-64. [PMID: 22614117 DOI: 10.3892/ijo.2012.1486] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2012] [Accepted: 04/12/2012] [Indexed: 12/28/2022] Open
Abstract
Endometrial carcinoma is the most common gynaecological malignancy. There is however a lack of curative therapies, especially for patients diagnosed with late stage, recurrent or aggressive disease, who have a poor prognosis. Interleukin (IL) 11 is a pleiotropic cytokine that has a role in a number of cancers including colon and breast cancer. IL11 was recently found to be upregulated in endometrial cancers, however the function of IL11 in endometrial cancer is not known. This study aimed to determine the effects of IL11 on endometrial cancer cell proliferation, adhesion and migration. Three endometrial cancer cell lines, Ishikawa, HEC-1A and AN3CA (derived from endometrial cancers grade I, II and III, respectively), were used to determine the effect of IL11 on endometrial cancer cell function. Cell proliferation and viability were assessed by BrdU and Wst-1 assays. Cell adhesion to the extracellular matrix proteins fibronectin, collagen I and IV, vitronectin and laminin was assessed. Modified boyden chambers were utilized to access IL11 action on migration and invasion, respectively. The specific effect of IL11 action on these processes was determined using a unique IL11 inhibitor. IL11 phosphorylated (p)-STAT3 protein abundance in all 3 cell lines but had no effect on pERK and pAKT abundance. Similarly, IL11 had no effect on cell proliferation and viability but increased adhesion of ANC3A cells to fibronectin while having no effect on the other extracellular matrix proteins. IL11 did not alter the adhesive properties of the Ishikawa and HEC-1A cells. In the AN3CA cells, IL11 treatment resulted in a 50% increase in migration and co-treatment with the specific IL11 inhibitor or a STAT3 inhibitor abolished the effect. This study shows a role for IL11 in endometrial cancer and suggests IL11 may be involved in endometrial cancer development and thus may be useful as a therapeutic target.
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Affiliation(s)
- Virginia Lay
- Prince Henry's Institute of Medical Research, Clayton, VIC 3168, Australia
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Lampropoulos P, Zizi-Sermpetzoglou A, Rizos S, Kostakis A, Nikiteas N, Papavassiliou AG. Prognostic significance of transforming growth factor beta (TGF-β) signaling axis molecules and E-cadherin in colorectal cancer. Tumour Biol 2012; 33:1005-14. [PMID: 22278155 DOI: 10.1007/s13277-012-0333-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Accepted: 01/11/2012] [Indexed: 11/28/2022] Open
Abstract
The transforming growth factor beta (TGF-β) signaling pathway has been considered both a tumor suppressor and a cancer promoter. Additionally, downregulation of cell adhesion molecules such as E-cadherin plays an important role in the metastatic potential of colorectal cancer (CRC). The aim of the present study was to evaluate TGF-β, TGF-β type I receptor (TGF-βR1), TGF-β type II receptor (TGF-βR2), Smad4, pSmad2/3, and E-cadherin expression in colorectal carcinoma and to correlate the obtained data with other standard prognostic parameters, such as disease stage, metastases, and patient survival. TGF-β, TGF-βR1, TGF-βR2, Smad4, pSmad2/3, and E-cadherin expression was evaluated immunohistochemically in 195 unrelated CRC specimens and the results subjected to various statistical analyses. TGF-β was expressed in 71.28%, TGF-βR1 in 61.0%, TGF-βR2 in 54.4%, Smad4 in 61.5%, pSmad2/3 in 71.3%, and E-cadherin in 50.26% of the colorectal carcinoma samples tested. The correlation of immunoexpression with the clinicopathological parameters of CRC revealed that the high expression of TGF-β and low expression of TGF-βR1, TGF-βR2, Smad4, pSmad2/3, and E-cadherin were correlated with tumor-node-metastasis (TNM) stage of disease. High TGF-β expression and low TGF-βR1, TGF-βR2, Smad4, and pSmad2/3 expression were also correlated with lymph node metastasis. The Kaplan-Meier survival curves demonstrated a clear association of cancer-specific overall survival with high TGF-β, as well as low TGF-βR1, TGF-βR2, Smad4, pSmad2/3, and E-cadherin expression. Our results suggest that TGF-β, TGF-βR1, TGF-βR2, Smad4, pSmad2/3, and E-cadherin are closely related to TNM stage of CRC. Moreover, TGF-β, TGF-βR2, Smad4, pSmad2/3, and E-cadherin emerge as valuable independent biomarkers of prognosis in CRC patients.
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Hong SM, Li A, Olino K, Wolfgang CL, Herman JM, Schulick RD, Iacobuzio-Donahue C, Hruban RH, Goggins M. Loss of E-cadherin expression and outcome among patients with resectable pancreatic adenocarcinomas. Mod Pathol 2011; 24:1237-47. [PMID: 21552209 PMCID: PMC3155013 DOI: 10.1038/modpathol.2011.74] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Only a minority of patients who undergo surgical resection for pancreatic ductal adenocarcinoma are cured. Since patient outcome is not reliably predicted using pathological factors (tumor stage, differentiation, and resection margin status) alone, markers of tumor behavior are needed. One candidate predictor of pancreatic cancer outcome is E-cadherin status. CDH1 is a tumor suppressor gene encoding an important cell adhesion molecule (E-cadherin). The aim of this study was to determine if, among patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma, loss of E-cadherin expression was an independent predictor of poor outcome. We examined patterns of loss of E-cadherin by immunohistochemistry in tissue microarrays of 329 surgically resected pancreatic ductal adenocarcinomas. E-cadherin expression was then correlated with outcome. Kaplan-Meier analysis and Cox proportional hazards regression modeling were used to assess the mortality risk. One hundred forty-one pancreatic adenocarcinomas (43%) had partial or complete loss of E-cadherin expression within the analyzed tissue cores. In most instances (134 cases, 41%), this loss was partial. Patients whose pancreatic adenocarcinomas had either complete loss (n=7; median survival, 5.5 months) or partial loss (n=134; 12.7 months) of E-cadherin expression had significantly worse median survival than those with uniformly intact E-cadherin expression (n=188; 18.5 months) by univariate (P=0.002) and multivariate (P=0.006) analyses. In subgroup analysis, patients with poorly differentiated cancers had a worse prognosis if their cancers had partial loss of E-cadherin expression (P=0.02). Among patients undergoing pancreaticoduodenectomy for pancreatic ductal adenocarcinoma, partial loss of tumoral E-cadherin expression is an independent predictor of poor outcome.
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Affiliation(s)
- Seung-Mo Hong
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Ang Li
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Kelly Olino
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Christopher L. Wolfgang
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Joseph M. Herman
- Department of Radiation Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Richard D. Schulick
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Christine Iacobuzio-Donahue
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Ralph H. Hruban
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Michael Goggins
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
- Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
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Hepatocyte growth factor inhibits anoikis of pancreatic carcinoma cells through phosphatidylinositol 3-kinase pathway. Pancreas 2011; 40:608-14. [PMID: 21499215 DOI: 10.1097/mpa.0b013e318214fa6c] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
OBJECTIVES Escape from anoikis, apoptosis induced by loss of cell-cell or cell-extracellular matrix interactions, is important in tumor invasion and metastasis. Hepatocyte growth factor (HGF) is known to play a pivotal role in pancreatic carcinomas. This study aimed to determine the antianoikis effect of HGF in pancreatic carcinoma cells. METHODS Antianoikis effect of HGF was evaluated in human pancreatic carcinoma cells in nonadherent culture with or without anti-E-cadherin antibody. Signal pathways were investigated by Western blot analysis and inhibition assay using inhibitors for phosphatidylinositol 3-kinase and p38. RESULTS Pancreatic carcinoma cells underwent anoikis in nonadherent culture. However, some of the carcinoma cells survived by forming aggregations in suspension. Anti-E-cadherin antibody dissociated the aggregations, and the separated cells underwent additional anoikis. Hepatocyte growth factor inhibited anoikis irrespective of E-cadherin-mediated cell-cell contact. Inhibition of the phosphatidylinositol 3-kinase/Akt pathway abolished the antianoikis effect of HGF. Phosphorylation of Akt was induced by HGF, and the phosphorylated Akt persisted even when E-cadherin was inhibited. CONCLUSIONS Hepatocyte growth factor inhibits anoikis of pancreatic carcinoma cells through phosphatidylinositol 3-kinase pathway in which activation of Akt may be involved. It is thus supposed that HGF may have a potent role in invasion and metastasis of pancreatic carcinoma cells by exerting its antianoikis effect.
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Chien MH, Chou LSS, Chung TT, Lin CH, Chou MY, Weng MS, Yang SF, Chen MK. Effects of E-cadherin (CDH1) gene promoter polymorphisms on the risk and clinicopathologic development of oral cancer. Head Neck 2011; 34:405-11. [PMID: 21472888 DOI: 10.1002/hed.21746] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2010] [Revised: 12/18/2010] [Accepted: 01/04/2011] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND This study investigates the association between polymorphism in the E-cadherin/CDH1 promoter region and the risk and progression of oral cancer. METHODS Genetic polymorphisms of CDH1-160 and -347 were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 347 noncancer controls and in 251 patients with oral cancer. RESULTS The statistical analysis showed that subjects with at least 1 varied GA allele of CDH1-347 polymorphic genotypes or combinations of the CDH1-160 CA/-347 GGA, CDH1-160 CC/-347 GGA, or CDH1-160 CC/-347 GAGA genotypes had a significantly higher risk, whereas subjects with CDH1-160 C/A or A/A had a significantly lower risk of developing oral cancer than those with wild-type genotypes. Furthermore, elderly patients with the CDH1-347 G/GA or GA/GA genotype were associated with a higher incidence in lymph node metastasis than were those with the G/G genotype. CONCLUSIONS These results suggest that CDH1-347 polymorphisms are associated with increased risks of oral cancer, and may be a predictive factor for tumor lymph node metastasis.
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Chien MH, Yeh KT, Li YC, Hsieh YH, Lin CH, Weng MS, Kuo WH, Yang SF. Effects of E-cadherin (CDH1) gene promoter polymorphisms on the risk and clinicopathological development of hepatocellular carcinoma. J Surg Oncol 2011; 104:299-304. [PMID: 21462191 DOI: 10.1002/jso.21929] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2010] [Accepted: 03/11/2011] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND OBJECTIVES Hepatocellular carcinoma (HCC) is one of the most frequent malignant neoplasms worldwide, and is the second leading cause of cancer death in Taiwan. E-cadherin is an epithelial cell adhesion molecule, and decreased E-cadherin expression in HCC is associated with a poor prognosis. This study investigates the effects of single nucleotide polymorphisms (SNPs) in the E-cadherin/CDH1 gene promoter on the risk and clinicopathological characteristics of HCC METHODS: 131 HCC patients and 347 controls were recruited for this study. Genetic polymorphisms of CDH1-160 and -347 were analyzed by PCR-RFLP genotyping analysis. RESULTS After adjusting for other confounders, results show that individuals with the CDH1-347G/GA or GA/GA polymorphic genotypes had a significantly higher risk of developing HCC than those with the wild-type (G/G) genotype (adjusted odds ratio = 2.477; 95%CI: 1.421-4.319). Furthermore, patients with HCC with at least one mutant A allele of CDH1-160 had a 4.031-fold risk of progressing to stage III or IV. CONCLUSIONS This study shows that SNPs in CDH1-347 gene are associated with an increased risk of HCC, and at least one mutant A allele of CDH1-160 gene is associated with the development of stage III or IV of HCC in Taiwanese.
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Slug enhances invasion ability of pancreatic cancer cells through upregulation of matrix metalloproteinase-9 and actin cytoskeleton remodeling. J Transl Med 2011; 91:426-38. [PMID: 21283078 PMCID: PMC3125102 DOI: 10.1038/labinvest.2010.201] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Slug, a member of the Snail family of transcription factors, has a crucial role in the regulation of epithelial-mesenchymal transition (EMT) by suppressing several epithelial markers and adhesion molecules, including E-cadherin. A recent study demonstrated that no relationship exists between Slug and E-cadherin in pancreatic cancer. Another study showed that in malignant mesothelioma effusions Slug was associated with matrix metalloproteinase (MMP) expression, but that there was no association with E-cadherin. F-ascin is an actin-bundling protein involved in filopodia assembly and cancer invasion and metastasis of multiple epithelial cancer types. In this study, we investigated Slug, E-cadherin, and MMP-9 expression using immunohistochemistry in 60 patients with pancreatic cancer and their correlation with carcinoma invasion and metastasis. Additionally, we observed the effects of Slug on invasion and metastasis in the pancreatic cancer cell line PANC-1. Alterations in Slug, MMP-9, and E-cadherin were determined by RT-PCR, western blot, and immunohistochemistry. Alterations in MMP-9 and F-actin cytoskeleton were determined by immunofluorescence staining, flow cytometry (FCM), or gelatin zymography. Slug, E-cadherin, and MMP-9 expression in pancreatic cancer was significantly associated with lymph node metastases and we found a significant correlation between Slug and MMP-9 expression; however, no significant correlation was observed between Slug and E-cadherin expression. Slug transfection significantly increased invasion and metastasis in PANC-1 cells and orthotopic tumor of mouse in vivo, and significantly upregulated and activated MMP-9; however, there was no effect on E-cadherin expression. Slug promoted the formation of lamelliopodia or filopodia in PANC-1 cells. The intracellular F-actin and MMP-9 was increased and relocated to the front of the extending pseudopodia from the perinuclear pool in Slug-transfected PANC-1 cells. These results suggest that Slug promotes migration and invasion of PANC-1 cells, which may correlate with the reorganization of MMP-9 and remodeling of the F-actin cytoskeleton, but not with E-cadherin expression.
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A short primer on the calcium sensing receptor: an important cog in the colon cancer wheel? Dig Dis Sci 2011; 56:279-84. [PMID: 20556514 DOI: 10.1007/s10620-010-1295-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2010] [Accepted: 05/25/2010] [Indexed: 01/26/2023]
Abstract
The gastrointestinal (GI) tract handles a complex task of nutrient absorption and excretion of excess fluid, electrolytes, and toxic substances. GI epithelium is under constant proliferation and renewal. Differentiation of colonocytes occurs as they migrate from the basal layer to the apex of the crypt. Cells of the basal layer are highly proliferative but less differentiated, whereas apical cells are highly differentiated but non-proliferative. Alterations of this intricate process lead to abnormal proliferation and differentiation of colorectal mucosa leading to development of polyps and neoplasia. The effects of calcium (Ca) on colorectal mucosal growth have been extensively studied after the discovery of the calcium sensing receptor (CaSR). Fluctuation in extracellular Ca can induce hyperproliferation or quiescence. Disruption in the function of CaSR and/or changes in the level of CaSR expression can cause loss of growth suppressing effects of extracellular Ca. This review addresses the role of Ca and CaSR in the physiology and pathophysiology of colonocyte proliferation.
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Significance of dysadherin and E-cadherin expression in differentiated-type gastric carcinoma with submucosal invasion. Hum Pathol 2011; 42:558-67. [PMID: 21239043 DOI: 10.1016/j.humpath.2010.08.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2010] [Revised: 08/06/2010] [Accepted: 08/20/2010] [Indexed: 11/24/2022]
Abstract
Dysadherin is a cancer-associated cell membrane glycoprotein that down-regulates E-cadherin and plays important roles in tumor progression and metastasis. Differentiated-type gastric carcinoma can be classified into 2 histologic subtypes according to the presence of poorly differentiated components: a mixed type (differentiated carcinoma with poorly differentiated components) and a pure type (purely differentiated-type adenocarcinoma). We studied the clinicopathologic features of 318 cases of differentiated-type gastric carcinoma with submucosal invasion and evaluated the immunohistochemical expression of dysadherin and E-cadherin. We also evaluated 46 cases of metastatic lymph nodes. Tumors with combined dysadherin-positive (≥50%) expression and E-cadherin-negative (<50%) expression had significantly higher proportions of the moderately differentiated type, deeper submucosal invasion, positivity of lymphatic permeation, and positivity of lymph node metastasis than tumors with other combinations of dysadherin and E-cadherin expression (P = .0009, P = .0015, P = .0273, and P = .0187, respectively). Moreover, the frequency of dysadherin-positive (≥50%) expression was higher in the mixed type (60.3%) than in the pure type (12.4%) (P < .0001), whereas the frequency of E-cadherin-negative (<50%) expression was higher in the mixed type (84.5%) than in the pure type (50.5%) (P < .0001). The frequency of dysadherin expression in the metastatic lymph nodes (80.4%) was significantly higher than that in the primary tumors (45.7%) (P = .001). Dysadherin-positive (≥50%) expression and E-cadherin-negative (<50%) expression may be correlated with the mixed type. Combined dysadherin-positive (≥50%) expression and E-cadherin-negative (<50%) expression may be valuable information for predicting aggressive tumor behavior.
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Niinaka Y, Harada K, Fujimuro M, Oda M, Haga A, Hosoki M, Uzawa N, Arai N, Yamaguchi S, Yamashiro M, Raz A. Silencing of autocrine motility factor induces mesenchymal-to-epithelial transition and suppression of osteosarcoma pulmonary metastasis. Cancer Res 2010; 70:9483-93. [PMID: 20978190 DOI: 10.1158/0008-5472.can-09-3880] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Phosphoglucose isomerase (PGI) is a multifunctional enzyme that functions in glucose metabolism as a glycolytic enzyme catalyzing an interconversion between glucose and fructose inside the cell, while it acts as cytokine outside the cell, with properties that include autocrine motility factor (AMF)-regulating tumor cell motility. Overexpression of AMF/PGI induces epithelial-to-mesenchymal transition with enhanced malignancy. Recent studies have revealed that silencing of AMF/PGI resulted in mesenchymal-to-epithelial transition (MET) of human lung fibrosarcoma cells and breast cancer cells with reduced malignancy. Here, we constructed a hammerhead ribozyme specific against GUC triplet at the position G390 in the human, mouse, and rat AMF/PGI mRNA sequence. Mesenchymal human osteosarcoma MG-63, HS-Os-1, and murine LM8 cells were stably transfected with the ribozyme specific for AMF/PGI. The stable transfectant cells showed effective downregulation of AMF/PGI expression and subsequent abrogation of AMF/PGI secretion, which resulted in morphologic change with reduced growth, motility, and invasion. Silencing of AMF/PGI induced MET, in which upregulation of E-cadherin and cytokeratins, as well as downregulation of vimentin, were noted. The MET guided by AMF/PGI gene silencing induced osteosarcoma MG-63 to terminally differentiate into mature osteoblasts. Furthermore, MET completely suppressed the tumor growth and pulmonary metastasis of LM8 cells in nude mice. Thus, acquisition of malignancy might be completed in part by upregulation of AMF/PGI, and waiver of malignancy might also be controlled by downregulation of AMF/PGI.
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Affiliation(s)
- Yasufumi Niinaka
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Japan.
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