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1
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Zhou K, Liu Y, Tang C, Zhu H. Pancreatic Cancer: Pathogenesis and Clinical Studies. MedComm (Beijing) 2025; 6:e70162. [PMID: 40182139 PMCID: PMC11965705 DOI: 10.1002/mco2.70162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 03/08/2025] [Accepted: 03/12/2025] [Indexed: 04/05/2025] Open
Abstract
Pancreatic cancer (PC) is a highly lethal malignancy, with pancreatic ductal adenocarcinoma (PDAC) being the most common and aggressive subtype, characterized by late diagnosis, aggressive progression, and resistance to conventional therapies. Despite advances in understanding its pathogenesis, including the identification of common genetic mutations (e.g., KRAS, TP53, CDKN2A, SMAD4) and dysregulated signaling pathways (e.g., KRAS-MAPK, PI3K-AKT, and TGF-β pathways), effective therapeutic strategies remain limited. Current treatment modalities including chemotherapy, targeted therapy, immunotherapy, radiotherapy, and emerging therapies such as antibody-drug conjugates (ADCs), chimeric antigen receptor T (CAR-T) cells, oncolytic viruses (OVs), cancer vaccines, and bispecific antibodies (BsAbs), face significant challenges. This review comprehensively summarizes these treatment approaches, emphasizing their mechanisms, limitations, and potential solutions, to overcome these bottlenecks. By integrating recent advancements and outlining critical challenges, this review aims to provide insights into future directions and guide the development of more effective treatment strategies for PC, with a specific focus on PDAC. Our work underscores the urgency of addressing the unmet needs in PDAC therapy and highlights promising areas for innovation in this field.
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Affiliation(s)
- Kexun Zhou
- Department of Medical OncologyCancer CenterWest China HospitalSichuan UniversityChengduChina
| | - Yingping Liu
- Department of RadiotherapyCancer HospitalChinese Academy of Medical SciencesBeijingChina
| | - Chuanyun Tang
- The First Clinical Medical College of Nanchang UniversityNanchang UniversityNanchangChina
| | - Hong Zhu
- Department of Medical OncologyCancer CenterWest China HospitalSichuan UniversityChengduChina
- Division of Abdominal Tumor Multimodality TreatmentCancer CenterWest China HospitalSichuan UniversityChengduChina
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2
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Ye X, Wu Y, Zhang H. Emerging Claudin18.2-targeting Therapy for Systemic Treatment of Gastric Cancer: Seeking Nobility Amidst Danger. Anticancer Agents Med Chem 2025; 25:223-231. [PMID: 39364863 DOI: 10.2174/0118715206329892240927081033] [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: 06/14/2024] [Revised: 09/12/2024] [Accepted: 09/16/2024] [Indexed: 10/05/2024]
Abstract
Gastric cancer in advanced stages lacked effective treatment options. claudin18.2 (CLDN18.2) is a membrane protein that is crucial for close junctions in the differentiated epithelial cells of the gastric mucosa, playing a vital role in barrier function, and can be hardly recognized by immune cells due to its polarity pattern. As the polarity of gastric tumor cells changes, claudin18.2 is exposed on the cell surface, resulting in immune system recognition, and making it an ideal target. In this review, we summarized the expression regulation mechanism of claudin18.2 both in normal cells and malignant tumor cells. Besides, we analyzed the available clinical results and potential areas for future research on claudin18.2-positive gastric cancer and claudin18.2-targeting therapy. In conclusion, claudin18.2 is an ideal target for gastric cancer treatment, and the claudin18.2-targeting therapy has changed the treatment pattern of gastric cancer.
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Affiliation(s)
- Xueshuai Ye
- School of Clinical Medicine, Hebei University of Engineering, Handan, 056002, China
| | - Yongqiang Wu
- Gene Editing Research Center, Hebei University of Science and Technology, Shijiazhuang, 050000, China
| | - Haiqiang Zhang
- Department of Surgery, The Second Hospital of Hebei Medical University, 215 West Heping Road, Shijiazhuang, 050051, China
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3
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Jeon H, Sterpi M, Mo C, Bteich F. Claudins: from gatekeepers of epithelial integrity to potential targets in hepato-pancreato-biliary cancers. Front Oncol 2024; 14:1454882. [PMID: 39391254 PMCID: PMC11464258 DOI: 10.3389/fonc.2024.1454882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 08/22/2024] [Indexed: 10/12/2024] Open
Abstract
Claudins, a family of tetraspan transmembrane proteins, are critical to the integrity of tight junctions in epithelia and endothelia, influencing cellular processes such as development, differentiation, and apoptosis. Abnormal claudin expression is associated with various malignancies, particularly affecting tissue architecture and potentially facilitating tumor invasion and metastasis. In this comprehensive review, we explore the multifaceted functions of claudins: their expression, specific roles in cancer with a focus on hepato-pancreato-biliary malignancies and highlight their potential as therapeutic targets. We discuss current claudin-targeted therapies, including monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engager and chimeric antigen receptor T-cell therapies. These approaches show promise in pre-clinical and clinical studies, particularly in hepato-pancreato-biliary cancers with large unmet needs. Despite these early signs of efficacy, challenges remain in effectively targeting these proteins due to their structural resemblance and overlapping functions.
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Affiliation(s)
- Hyein Jeon
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY, United States
| | - Michelle Sterpi
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY, United States
| | - Christiana Mo
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY, United States
| | - Fernand Bteich
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY, United States
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4
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Du F, Xie Y, Wu S, Ji M, Dong B, Zhu C. Expression and Targeted Application of Claudins Family in Hepatobiliary and Pancreatic Diseases. J Hepatocell Carcinoma 2024; 11:1801-1821. [PMID: 39345937 PMCID: PMC11439345 DOI: 10.2147/jhc.s483861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 09/12/2024] [Indexed: 10/01/2024] Open
Abstract
Hepatobiliary and pancreatic diseases are becoming increasingly common worldwide and associated cancers are prone to recurrence and metastasis. For a more accurate treatment, new therapeutic strategies are urgently needed. The claudins (CLDN) family comprises a class of membrane proteins that are the main components of tight junctions, and are essential for forming intercellular barriers and maintaining cellular polarity. In mammals, the claudin family contains at least 27 transmembrane proteins and plays a major role in mediating cell adhesion and paracellular permeability. Multiple claudin proteins are altered in various cancers, including gastric cancer (GC), esophageal cancer (EC), hepatocellular carcinoma (HCC), pancreatic cancer (PC), colorectal cancer (CRC) and breast cancer (BC). An increasing number of studies have shown that claudins are closely associated with the occurrence and development of hepatobiliary and pancreatic diseases. Interestingly, claudin proteins exhibit different effects on cancer progression in different tumor tissues, including tumor suppression and promotion. In addition, various claudin proteins are currently being studied as potential diagnostic and therapeutic targets, including claudin-3, claudin-4, claudin-18.2, etc. In this article, the functional phenotype, molecular mechanism, and targeted application of the claudin family in hepatobiliary and pancreatic diseases are reviewed, with an emphasis on claudin-1, claudin-4, claudin-7 and claudin-18.2, and the current situation and future prospects are proposed.
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Affiliation(s)
- Fangqian Du
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Yuwei Xie
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Shengze Wu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Mengling Ji
- Department of Surgery, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Bingzi Dong
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Chengzhan Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
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5
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Zeng Y, Lockhart AC, Jin RU. The preclinical discovery and development of zolbetuximab for the treatment of gastric cancer. Expert Opin Drug Discov 2024; 19:873-886. [PMID: 38919123 PMCID: PMC11938084 DOI: 10.1080/17460441.2024.2370332] [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: 03/31/2024] [Revised: 06/04/2024] [Accepted: 06/17/2024] [Indexed: 06/27/2024]
Abstract
INTRODUCTION Gastric cancer remains a formidable challenge in oncology with high mortality rates and few advancements in treatment. Claudin-18.2 (CLDN18.2) is a tight junction protein primarily expressed in the stomach and is frequently overexpressed in certain subsets of gastric cancers. Targeting CLDN18.2 with monoclonal antibodies, such as zolbetuximab (IMAB362), has shown promising efficacy results in combination with chemotherapy. AREAS COVERED The molecular cell biology of CLDN18.2 is discussed along with studies demonstrating the utility of CLDN18.2 expression as a biomarker and therapeutic target. Important clinical studies are reviewed, including Phase III trials, SPOTLIGHT and GLOW, which demonstrate the efficacy of zolbetuximab in combination with chemotherapy in patients with CLDN18.2-positive advanced gastric cancer. EXPERT OPINION CLDN18.2 is involved in gastric differentiation through maintenance of epithelial barrier function and coordination of signaling pathways, and its expression in gastric cancers reflects a 'gastric differentiation' program. Targeting Claudin-18.2 represents the first gastric cancer specific 'targeted' treatment. Further studies are needed to determine its role within current gastric cancer treatment sequencing, including HER2-targeted therapies and immunotherapies. Management strategies will also be needed to better mitigate zolbetuximab-related treatment side effects, including gastrointestinal (GI) toxicities.
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Affiliation(s)
- Yongji Zeng
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, USA
| | - A. Craig Lockhart
- Division of Hematology/Oncology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Ramon U. Jin
- Section of Hematology/Oncology, Department of Medicine, Baylor College of Medicine, Houston, USA
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6
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Brunet M, Vargas C, Fanjul M, Varry D, Hanoun N, Larrieu D, Pieruccioni L, Labrousse G, Lulka H, Capilla F, Ricard A, Selves J, Couvelard A, Gigoux V, Cordelier P, Guillermet-Guibert J, Dufresne M, Torrisani J. The E3 ubiquitin ligase TRIP12 is required for pancreatic acinar cell plasticity and pancreatic carcinogenesis. J Pathol 2024; 263:466-481. [PMID: 38924548 DOI: 10.1002/path.6298] [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: 11/14/2023] [Revised: 03/15/2024] [Accepted: 04/23/2024] [Indexed: 06/28/2024]
Abstract
The E3 ubiquitin ligase thyroid hormone receptor interacting protein 12 (TRIP12) has been implicated in pancreatic adenocarcinoma (PDAC) through its role in mediating the degradation of pancreas transcription factor 1a (PTF1a). PTF1a is a transcription factor essential for the acinar differentiation state that is notably diminished during the early steps of pancreatic carcinogenesis. Despite these findings, the direct involvement of TRIP12 in the onset of pancreatic cancer has yet to be established. In this study, we demonstrated that TRIP12 protein was significantly upregulated in human pancreatic preneoplastic lesions. Furthermore, we observed that TRIP12 overexpression varied within PDAC samples and PDAC-derived cell lines. We further demonstrated that TRIP12 was required for PDAC-derived cell growth and for the expression of E2F-targeted genes. Acinar-to-ductal cell metaplasia (ADM) is a reversible process that reflects the high plasticity of acinar cells. ADM becomes irreversible in the presence of oncogenic Kras mutations and leads to the formation of preneoplastic lesions. Using two genetically modified mouse models, we showed that a loss of TRIP12 prevented acini from developing ADM in response to pancreatic injury. With two additional mouse models, we further discovered that a depletion of TRIP12 prevented the formation of KrasG12D-induced preneoplastic lesions and impaired metastasis formation in the presence of mutated KrasG12D and Trp53R172H genes. In summary our study identified an overexpression of TRIP12 from the early stages of pancreatic carcinogenesis and proposed this E3 ubiquitin ligase as a novel regulator of acinar plasticity with an important dual role in initiation and metastatic steps of PDAC. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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MESH Headings
- Animals
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/enzymology
- Humans
- Acinar Cells/pathology
- Acinar Cells/metabolism
- Acinar Cells/enzymology
- Ubiquitin-Protein Ligases/metabolism
- Ubiquitin-Protein Ligases/genetics
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/enzymology
- Metaplasia/pathology
- Metaplasia/metabolism
- Cell Plasticity
- Carcinogenesis/genetics
- Carcinogenesis/metabolism
- Mice
- Cell Line, Tumor
- Cell Proliferation
- Mice, Knockout
- Gene Expression Regulation, Neoplastic
- Precancerous Conditions/pathology
- Precancerous Conditions/genetics
- Precancerous Conditions/metabolism
- Precancerous Conditions/enzymology
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/pathology
- Cell Transformation, Neoplastic/metabolism
- Carrier Proteins
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Affiliation(s)
- Manon Brunet
- CRCT, Université de Toulouse, INSERM, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France
| | - Claire Vargas
- CRCT, Université de Toulouse, INSERM, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
| | - Marjorie Fanjul
- CRCT, Université de Toulouse, INSERM, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
| | - Damien Varry
- CRCT, Université de Toulouse, INSERM, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
| | - Naïma Hanoun
- CRCT, Université de Toulouse, INSERM, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
| | - Dorian Larrieu
- CRCT, Université de Toulouse, INSERM, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
| | - Laetitia Pieruccioni
- Centre de recherches RESTORE, Université de Toulouse, INSERM, CNRS, EFS, ENVT, Toulouse, France
| | - Guillaume Labrousse
- CRCT, Université de Toulouse, INSERM, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
| | - Hubert Lulka
- CRCT, Université de Toulouse, INSERM, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
| | - Florence Capilla
- Service d'Histopathologie expérimentale, INSERM US006-CREFRE, Toulouse, France
| | - Alban Ricard
- CRCT, Université de Toulouse, INSERM, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
| | - Janick Selves
- Département de Pathologie, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France
| | - Anne Couvelard
- Département de Pathologie Beaujon-Bichat, Hôpital Bichat, APHP and Université Paris Cité, Paris, France
| | - Véronique Gigoux
- CRCT, Université de Toulouse, INSERM, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
| | - Pierre Cordelier
- CRCT, Université de Toulouse, INSERM, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
| | - Julie Guillermet-Guibert
- CRCT, Université de Toulouse, INSERM, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
| | - Marlène Dufresne
- CRCT, Université de Toulouse, INSERM, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
| | - Jérôme Torrisani
- CRCT, Université de Toulouse, INSERM, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
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7
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Jin WM, Zhu Y, Cai ZQ, He N, Yu ZQ, Li S, Yang JY. Progress of Clinical Studies Targeting Claudin18.2 for the Treatment of Gastric Cancer. Dig Dis Sci 2024; 69:2631-2647. [PMID: 38769225 DOI: 10.1007/s10620-024-08435-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 04/10/2024] [Indexed: 05/22/2024]
Abstract
Claudin18.2 is a tight junction protein, highly selective, generally expressed only in normal gastric mucosal epithelial cells, which can effectively maintain the polarity of epithelial and endothelial cells, thus effectively regulating the permeability and conductance of the paracellular pathway. Abnormal expression of Claudin18.2 can occur in various primary malignant tumors, especially gastrointestinal tumors, and even in metastatic foci. It regulates its expression by activating the aPKC/MAPK/AP-1 pathway, and therefore, the Claudin18.2 protein is a pan-cancer target expressed in primary and metastatic lesions in human cancer types. Zolbetuximab (IMAB362), an antibody specific for Claudin18.2, has been successfully tested in a phase III clinical trial, and the results of the study showed that combining Zolbetuximab with chemotherapy notably extends patients' survival and is expected to be a potential first-line treatment for patients with Claudin18.2(+)/HER-2(-) gastric cancer. Here, we systematically describe the biological properties and oncogenic effects of Claudin18.2, centering on its clinical-pathological aspects and the progress of drug studies in gastric cancer, which can help to further explore its clinical value.
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Affiliation(s)
- Wu-Mei Jin
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China
| | - Yan Zhu
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China
| | - Zhi-Qiang Cai
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China
| | - Na He
- Department of General, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China
| | - Zhi-Qiong Yu
- Department of Respiratory, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China
| | - Shuang Li
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China
| | - Ji-Yuan Yang
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China.
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8
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De Sanctis F, Dusi S, Caligola S, Anselmi C, Petrova V, Rossi B, Angelini G, Erdeljan M, Wöll S, Schlitter AM, Metzler T, Steiger K, Borok Z, Bailey P, Bauer A, Halin C, Boschi F, Giugno R, Canè S, Lawlor R, Corbo V, Scarpa A, Constantin G, Ugel S, Vascotto F, Sahin U, Türeci Ö, Bronte V. Expression of the membrane tetraspanin claudin 18 on cancer cells promotes T lymphocyte infiltration and antitumor immunity in pancreatic cancer. Immunity 2024; 57:1378-1393.e14. [PMID: 38749447 DOI: 10.1016/j.immuni.2024.04.021] [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: 05/24/2023] [Revised: 01/30/2024] [Accepted: 04/23/2024] [Indexed: 06/14/2024]
Abstract
Tumors weakly infiltrated by T lymphocytes poorly respond to immunotherapy. We aimed to unveil malignancy-associated programs regulating T cell entrance, arrest, and activation in the tumor environment. Differential expression of cell adhesion and tissue architecture programs, particularly the presence of the membrane tetraspanin claudin (CLDN)18 as a signature gene, demarcated immune-infiltrated from immune-depleted mouse pancreatic tumors. In human pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer, CLDN18 expression positively correlated with more differentiated histology and favorable prognosis. CLDN18 on the cell surface promoted accrual of cytotoxic T lymphocytes (CTLs), facilitating direct CTL contacts with tumor cells by driving the mobilization of the adhesion protein ALCAM to the lipid rafts of the tumor cell membrane through actin. This process favored the formation of robust immunological synapses (ISs) between CTLs and CLDN18-positive cancer cells, resulting in increased T cell activation. Our data reveal an immune role for CLDN18 in orchestrating T cell infiltration and shaping the tumor immune contexture.
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MESH Headings
- Animals
- Humans
- Mice
- Carcinoma, Non-Small-Cell Lung/immunology
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Pancreatic Ductal/immunology
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/metabolism
- Cell Line, Tumor
- Claudins/metabolism
- Claudins/genetics
- Gene Expression Regulation, Neoplastic/immunology
- Immunological Synapses/metabolism
- Immunological Synapses/immunology
- Lung Neoplasms/immunology
- Lung Neoplasms/pathology
- Lymphocyte Activation/immunology
- Lymphocytes, Tumor-Infiltrating/immunology
- Membrane Microdomains/metabolism
- Membrane Microdomains/immunology
- Mice, Inbred C57BL
- Pancreatic Neoplasms/immunology
- Pancreatic Neoplasms/pathology
- T-Lymphocytes, Cytotoxic/immunology
- Tumor Microenvironment/immunology
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Affiliation(s)
- Francesco De Sanctis
- Section of Immunology, Department of Medicine, University of Verona, Verona, Italy.
| | - Silvia Dusi
- Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | | | - Cristina Anselmi
- Section of Immunology, Department of Medicine, University of Verona, Verona, Italy
| | - Varvara Petrova
- Section of Immunology, Department of Medicine, University of Verona, Verona, Italy
| | - Barbara Rossi
- Section of General Pathology, Department of Medicine, University of Verona, Verona, Italy
| | - Gabriele Angelini
- Section of General Pathology, Department of Medicine, University of Verona, Verona, Italy
| | - Michael Erdeljan
- Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany
| | - Stefan Wöll
- Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany
| | - Anna Melissa Schlitter
- Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany; Institute of Pathology, School of Medicine, TUM, Munich, Germany
| | - Thomas Metzler
- Comparative Experimental Pathology (CEP), Institute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Katja Steiger
- Comparative Experimental Pathology (CEP), Institute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Zea Borok
- Department of Medicine, University of California, San Diego, San Diego, CA, USA
| | - Peter Bailey
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, Scotland
| | - Aline Bauer
- Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland
| | - Cornelia Halin
- Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland
| | - Federico Boschi
- Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy
| | - Rosalba Giugno
- Department of Computer Science, University of Verona, Verona, Italy
| | - Stefania Canè
- Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Rita Lawlor
- Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy; ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy
| | - Vincenzo Corbo
- Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy; ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy
| | - Aldo Scarpa
- ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy; Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - Gabriela Constantin
- Section of General Pathology, Department of Medicine, University of Verona, Verona, Italy; The Center for Biomedical Computing (CBMC), University of Verona, Verona, Italy
| | - Stefano Ugel
- Section of Immunology, Department of Medicine, University of Verona, Verona, Italy
| | - Fulvia Vascotto
- TRON-Translational Oncology at the University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
| | - Ugur Sahin
- Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany; University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Özlem Türeci
- Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany; University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
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9
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Nakayama I, Qi C, Chen Y, Nakamura Y, Shen L, Shitara K. Claudin 18.2 as a novel therapeutic target. Nat Rev Clin Oncol 2024; 21:354-369. [PMID: 38503878 DOI: 10.1038/s41571-024-00874-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2024] [Indexed: 03/21/2024]
Abstract
Claudin 18.2, a tight-junction molecule predominantly found in the nonmalignant gastric epithelium, becomes accessible on the tumour cell surface during malignant transformation, thereby providing an appealing target for cancer therapy. Data from two phase III trials testing the anti-claudin 18.2 antibody zolbetuximab have established claudin 18.2-positive advanced-stage gastric cancers as an independent therapeutic subset that derives benefit from the addition of this agent to chemotherapy. This development has substantially increased the percentage of patients eligible for targeted therapy. Furthermore, newer treatments, such as high-affinity monoclonal antibodies, bispecific antibodies, chimeric antigen receptor T cells and antibody-drug conjugates capable of bystander killing effects, have shown considerable promise in patients with claudin 18.2-expressing gastric cancers. This new development has resulted from drug developers moving beyond traditional targets, such as driver gene alterations or growth factors. In this Review, we highlight the biological rationale and explore the clinical activity of therapies that target claudin 18.2 in patients with advanced-stage gastric cancer and explore the potential for expansion of claudin 18.2-targeted therapies to patients with other claudin 18.2-positive solid tumours.
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Affiliation(s)
- Izuma Nakayama
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Changsong Qi
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yang Chen
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yoshiaki Nakamura
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
- International Research Promotion Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Lin Shen
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
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Xu Q, Jia C, Ou Y, Zeng C, Jia Y. Dark horse target Claudin18.2 opens new battlefield for pancreatic cancer. Front Oncol 2024; 14:1371421. [PMID: 38511141 PMCID: PMC10951399 DOI: 10.3389/fonc.2024.1371421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 02/23/2024] [Indexed: 03/22/2024] Open
Abstract
Pancreatic cancer is one of the deadliest malignant tumors, which is a serious threat to human health and life, and it is expected that pancreatic cancer may be the second leading cause of cancer death in developed countries by 2030. Claudin18.2 is a tight junction protein expressed in normal gastric mucosal tissues, which is involved in the formation of tight junctions between cells and affects the permeability of paracellular cells. Claudin18.2 is highly expressed in pancreatic cancer and is associated with the initiation, progression, metastasis and prognosis of cancer, so it is considered a potential therapeutic target. Up to now, a number of clinical trials for Claudin18.2 are underway, including solid tumors such as pancreatic cancers and gastric cancers, and the results of these trials have not yet been officially announced. This manuscript briefly describes the Claudia protein, the dual roles of Cluadin18 in cancers, and summarizes the ongoing clinical trials targeting Claudin18.2 with a view to integrating the research progress of Claudin18.2 targeted therapy. In addition, this manuscript introduces the clinical research progress of Claudin18.2 positive pancreatic cancer, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, CAR-T cell therapy, and hope to provide feasible ideas for the clinical treatment of Claudin18.2 positive pancreatic cancer.
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Affiliation(s)
- Qian Xu
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Department of Oncology, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Caiyan Jia
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Department of Oncology, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yan Ou
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Department of Oncology, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Chuanxiu Zeng
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Department of Oncology, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yingjie Jia
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Department of Oncology, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
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11
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Kubota Y, Shitara K. Zolbetuximab for Claudin18.2-positive gastric or gastroesophageal junction cancer. Ther Adv Med Oncol 2024; 16:17588359231217967. [PMID: 38188462 PMCID: PMC10768589 DOI: 10.1177/17588359231217967] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 11/15/2023] [Indexed: 01/09/2024] Open
Abstract
Claudins (CLDNs) are a family of major membrane proteins that form components of tight junctions. In normal tissues, CLDNs seal the intercellular space in the epithelial sheets to regulate tissue permeability, paracellular transport, and signal transduction. Claudin18.2 (CLDN18.2), a member of the CLDN family, is expressed specifically in gastric mucosal cells in normal tissue, and its expression is often retained in gastric cancer cells. CLDN18.2 is ectopically expressed in many cancers other than gastric cancer such as esophageal cancer, pancreatic cancer, biliary tract cancer, non-small-cell lung cancer, and ovarian cancer. Structurally, CLDN18.2 is localized on the apical side of the cell membrane and has extracellular loops capable of binding monoclonal antibodies. Upon malignant transformation, CLDN18.2 is exposed to the cell surface of the whole membrane, which enables the binding of monoclonal antibodies. Based on these characteristics, CLDN18.2 was considered to be optimal for target therapy, and zolbetuximab was developed which is a first-in-class chimeric immunoglobulin G1 monoclonal antibody highly specific for CLDN18.2. It binds to CLDN18.2 on the tumor cell surface and stimulates cellular and soluble immune effectors that activate antibody-dependent cytotoxicity and complement-dependent cytotoxicity. Recently, zolbetuximab combined with chemotherapy demonstrated a survival benefit in patients with CLDN18.2-positive and HER-2-negative gastric or gastroesophageal junction cancers in the global phase III SPOTLIGHT and GLOW trials. From these clinically meaningful results, CLDN18.2-targeting therapy including zolbetuximab has attracted a lot of attention. In this review, we summarize the clinical implications of CLDN18.2-positive gastric or GEJ cancer, and CLDN18.2-targeting therapy, mainly for zolbetuximab.
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Affiliation(s)
- Yohei Kubota
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan
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12
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Tao D, Guan B, Li H, Zhou C. Expression patterns of claudins in cancer. Heliyon 2023; 9:e21338. [PMID: 37954388 PMCID: PMC10637965 DOI: 10.1016/j.heliyon.2023.e21338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 10/17/2023] [Accepted: 10/19/2023] [Indexed: 11/14/2023] Open
Abstract
Claudins are four-transmembrane proteins, which were found in tight junctions. They maintain cell barriers and regulate cell differentiation and proliferation. They are involved in maintaining cellular polarity and normal functions. Different claudins show different expression patterns. The expression level and localization of claudins are altered in various cancers. They promote or inhibit proliferation, invasion, and migration of cancer cells through multiple signaling pathways. Therefore, claudins may serve as diagnostic markers, novel therapeutic targets, and prognostic risk factors. The important roles of claudins in cancer aroused our great interest. In the present review, we provide a summary of insights into expression patterns of claudins in cancer, which is more comprehensive and provides new ideas for further research.
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Affiliation(s)
- Daoyu Tao
- Department of Pathology, The Second Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Bingxin Guan
- Department of Pathology, The Second Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Hui Li
- Department of Pathology, The Second Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Chengjun Zhou
- Department of Pathology, The Second Hospital of Shandong University, Jinan, 250012, Shandong, China
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Chen J, Xu Z, Hu C, Zhang S, Zi M, Yuan L, Cheng X. Targeting CLDN18.2 in cancers of the gastrointestinal tract: New drugs and new indications. Front Oncol 2023; 13:1132319. [PMID: 36969060 PMCID: PMC10036590 DOI: 10.3389/fonc.2023.1132319] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 02/27/2023] [Indexed: 03/12/2023] Open
Abstract
Cancers of the gastrointestinal (GI) tract greatly contribute to the global cancer burden and cancer-related death. Claudin-18.2(CLDN18.2), a transmembrane protein, is a major component of tight junctions and plays an important role in the maintenance of barrier function. Its characteristic widespread expression in tumour tissues and its exposed extracellular loops make it an ideal target for researchers to develop targeted strategies and immunotherapies for cancers of the GI tract. In the present review, we focus on the expression pattern of CLDN18.2 and its clinical significance in GI cancer. We also discuss the tumour-promoting and/or tumour-inhibiting functions of CLDN18.2, the mechanisms regulating its expression, and the current progress regarding the development of drugs targeting CLDN18.2 in clinical research.
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Affiliation(s)
- Jinxia Chen
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Zhiyuan Xu
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Can Hu
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Shengjie Zhang
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Mengli Zi
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Li Yuan
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- *Correspondence: Li Yuan, ; Xiangdong Cheng,
| | - Xiangdong Cheng
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- *Correspondence: Li Yuan, ; Xiangdong Cheng,
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14
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Wang C, Wu N, Pei B, Ma X, Yang W. Claudin and pancreatic cancer. Front Oncol 2023; 13:1136227. [PMID: 36959784 PMCID: PMC10027734 DOI: 10.3389/fonc.2023.1136227] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 02/20/2023] [Indexed: 03/09/2023] Open
Abstract
Due to the lack of timely and accurate screening modalities and treatments, most pancreatic cancer (PCa) patients undergo fatal PCa progression within a short period since diagnosis. The claudin(CLDN) family is expressed specifically as tight junction structure in a variety of tumors, including PCa, and affects tumor progression by changing the cell junctions. Thus far, many of the 27 members of the claudin family, including claudin-18.2 and claudin-4, have significantly aberrantly expression in pancreatic tumors. In addition, some studies have confirmed the role of some claudin proteins in the diagnosis and treatment of pancreatic tumors. By targeting different targets of claudin protein and combining chemotherapy, further enhance tumor cell necrosis and inhibit tumor invasion and metastasis. Claudins can either promote or inhibit the development of pancreatic cancer, which indicates that the diagnosis and treatment of different kinds of claudins require to consider different biological characteristics. This literature summarizes the functional characteristics and clinical applications of various claudin proteins in Pca cells, with a focus on claudin-18.2 and claudin-4.
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Affiliation(s)
- Chen Wang
- Shanxi Medical University, Taiyuan, Shanxi, China
- Department of Gastroenterology, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Na Wu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Beibei Pei
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Xiaoyan Ma
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Wenhui Yang
- Department of Gastroenterology, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
- *Correspondence: Wenhui Yang,
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15
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Wang DW, Zhang WH, Danil G, Yang K, Hu JK. The role and mechanism of claudins in cancer. Front Oncol 2022; 12:1051497. [PMID: 36620607 PMCID: PMC9818346 DOI: 10.3389/fonc.2022.1051497] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 11/28/2022] [Indexed: 12/24/2022] Open
Abstract
Claudins are a tetraspan membrane protein multigene family that plays a structural and functional role in constructing tight junctions. Claudins perform crucial roles in maintaining cell polarity in epithelial and endothelial cell sheets and controlling paracellular permeability. In the last two decades, increasing evidence indicates that claudin proteins play a major role in controlling paracellular permeability and signaling inside cells. Several types of claudins are dysregulated in various cancers. Depending on where the tumor originated, claudin overexpression or underexpression has been shown to regulate cell proliferation, cell growth, metabolism, metastasis and cell stemness. Epithelial-to-mesenchymal transition is one of the most important functions of claudin proteins in disease progression. However, the exact molecular mechanisms and signaling pathways that explain why claudin proteins are so important to tumorigenesis and progression have not been determined. In addition, claudins are currently being investigated as possible diagnostic and treatment targets. Here, we discuss how claudin-related signaling pathways affect tumorigenesis, tumor progression, and treatment sensitivity.
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Affiliation(s)
- De-Wen Wang
- Gastric Cancer Center and Laboratory of Gastric Cancer, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China,State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Wei-Han Zhang
- Gastric Cancer Center and Laboratory of Gastric Cancer, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China,State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Galiullin Danil
- Gastric Cancer Center and Laboratory of Gastric Cancer, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China,State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China,Central Research Laboratory, Bashkir State Medical University, Ufa, Russia
| | - Kun Yang
- Gastric Cancer Center and Laboratory of Gastric Cancer, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China,State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Jian-Kun Hu
- Gastric Cancer Center and Laboratory of Gastric Cancer, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China,State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China,*Correspondence: Jian-Kun Hu,
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16
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Cao W, Xing H, Li Y, Tian W, Song Y, Jiang Z, Yu J. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy. Biomark Res 2022; 10:38. [PMID: 35642043 PMCID: PMC9153115 DOI: 10.1186/s40364-022-00385-1] [Citation(s) in RCA: 99] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 05/16/2022] [Indexed: 12/18/2022] Open
Abstract
The claudin18.2 (CLDN18.2) protein, an isoform of claudin18, a member of the tight junction protein family, is a highly selective biomarker with limited expression in normal tissues and often abnormal expression during the occurrence and development of various primary malignant tumors, such as gastric cancer/gastroesophageal junction (GC/GEJ) cancer, breast cancer, colon cancer, liver cancer, head and neck cancer, bronchial cancer and non-small-cell lung cancer. CLDN18.2 participates in the proliferation, differentiation and migration of tumor cells. Recent studies have identified CLDN18.2 expression as a potential specific marker for the diagnosis and treatment of these tumors. With its specific expression pattern, CLDN18.2 has become a unique molecule for targeted therapy in different cancers, especially in GC; for example, agents such as zolbetuximab (claudiximab, IMAB362), a monoclonal antibody (mAb) against CLDN18.2, have been developed. In this review, we outline recent advances in the development of immunotherapy strategies targeting CLDN18.2, including monoclonal antibodies (mAbs), bispecific antibodies (BsAbs), chimeric antigen receptor T (CAR-T) cells redirected to target CLDN18.2, and antibody–drug conjugates (ADCs).
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Affiliation(s)
- Weijie Cao
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Haizhou Xing
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yingmei Li
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Wenliang Tian
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yongping Song
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Zhongxing Jiang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Jifeng Yu
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
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Kyuno D, Takasawa A, Takasawa K, Ono Y, Aoyama T, Magara K, Nakamori Y, Takemasa I, Osanai M. Claudin-18.2 as a therapeutic target in cancers: cumulative findings from basic research and clinical trials. Tissue Barriers 2022; 10:1967080. [PMID: 34486479 PMCID: PMC8794250 DOI: 10.1080/21688370.2021.1967080] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 08/06/2021] [Accepted: 08/07/2021] [Indexed: 12/25/2022] Open
Abstract
Claudins are major components of tight junctions that maintain cell polarity and intercellular adhesion. The dynamics of claudins in cancer cells have attracted attention as a therapeutic target. During carcinogenesis, claudin expression is generally downregulated; however, overexpression of claudin-18.2 has been observed in several types of cancers. Upregulated and mislocalized claudin-18.2 expression in cancer cells has been suggested as a therapeutic target. Research on claudin-18.2 has revealed its involvement in carcinogenesis. Clinical trials using zolbetuximab, a monoclonal antibody targeting claudin-18.2, for patients with advanced cancer yielded positive results with few high-grade adverse events; thus, it is expected to be a novel and effective therapeutic. Here, we review current insights into the role that claudin-18.2 plays in basic cancer research and clinical applications. A better understanding of these roles will facilitate the development of new treatment strategies for cancer patients with poor prognoses.
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Affiliation(s)
- Daisuke Kyuno
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Japan
| | - Akira Takasawa
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
| | - Kumi Takasawa
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
| | - Yusuke Ono
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
| | - Tomoyuki Aoyama
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
| | - Kazufumi Magara
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
| | - Yuna Nakamori
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
| | - Ichiro Takemasa
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Japan
| | - Makoto Osanai
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
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Hwang JW, Jang SK, Lee DJ. Genomic analysis of pancreatic cancer reveals 3 molecular subtypes with different clinical outcomes. Medicine (Baltimore) 2021; 100:e24969. [PMID: 33832071 PMCID: PMC8036077 DOI: 10.1097/md.0000000000024969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 02/09/2021] [Accepted: 02/10/2021] [Indexed: 01/05/2023] Open
Abstract
ABSTRACT Pancreatic cancer has a very high mortality with a 5-year survival of <5%. The purpose of this study was to classify specific molecular subtypes associated with prognosis of pancreatic cancer using The Cancer Genome Atlas (TCGA) multiplatform genomic data.Multiplatform genomic data (N = 178), including gene expression, copy number alteration, and somatic mutation data, were obtained from cancer browser (https://genome-cancer.ucsc.edu, cohort: TCGA Pancreatic Cancer). Clinical data including survival results were analyzed. We also used validation cohort (GSE50827) to confirm the robustness of these molecular subtypes in pancreatic cancer.When we performed unsupervised clustering using TCGA gene expression data, we found three distinct molecular subtypes associated with different survival results. Copy number alteration and somatic mutation data showed different genomic patterns for these three subtypes. Ingenuity pathway analysis revealed that each subtype showed differentially altered pathways. Using each subtype-specific genes (200 were selected), we could predict molecular subtype in another cohort, confirming the robustness of these molecular subtypes of pancreatic cancer. Cox regression analysis revealed that molecular subtype is the only significant prognostic factor for pancreatic cancer (P = .042, 95% confidence interval 0.523-0.98).Genomic analysis of pancreatic cancer revealed 3 distinct molecular subtypes associated with different survival results. Using these subtype-specific genes and prediction model, we could predict molecular subtype associated with prognosis of pancreatic cancer.
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Affiliation(s)
- Ji Woong Hwang
- Department of Surgery, Kangnam Sacred Heart Hospital, Hallym University College of Medicine
| | - Soo Kyung Jang
- Department of Otolaryngology-Head and Neck Surgery, Division of Precision Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Dong Jin Lee
- Department of Otolaryngology-Head and Neck Surgery, Division of Precision Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
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19
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Yang W, Li L, Zhang K, Ma K, Gong Y, Zhou J, Gong K. CLDN10 associated with immune infiltration is a novel prognostic biomarker for clear cell renal cell carcinoma. Epigenomics 2020; 13:31-45. [PMID: 33203244 DOI: 10.2217/epi-2020-0256] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Aims: To identify the clinical roles of CLDN10 in clear cell renal cell carcinoma (ccRCC). Materials & methods: Using data from TCGA-KIRC, GEO DataSets and laboratory experiments to determine the prognostic and clinicopathological characteristics of CLDN10. Results: CLDN10 expression was remarkably reduced in ccRCC. Downregulated CLDN10 was related to metastasis and poor prognosis. Multivariate Cox analysis determined that elevated CLDN10 expression was independently correlated with longer OS and DFS. Moreover, CLDN10 expression was negatively associated with the methylation levels of cg10305311 and cg16275739. CLDN10 expression was also associated with naive CD4 and memory T-cell and dendritic cell infiltration. Conclusions: Immune-related CLDN10 is an independent prognostic biomarker of ccRCC. DNA hypermethylation plays an important role in decreased CLDN10 expression.
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Affiliation(s)
- Wuping Yang
- Department of Urology, Peking University First Hospital, Beijing 100034, P.R. China.,Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing 100034, P.R. China.,Institute of Urology, Peking University, Beijing 100034, P.R. China.,National Urological Cancer Center, Beijing 100034, P.R. China
| | - Lei Li
- Department of Urology, Peking University First Hospital, Beijing 100034, P.R. China.,Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing 100034, P.R. China.,Institute of Urology, Peking University, Beijing 100034, P.R. China.,National Urological Cancer Center, Beijing 100034, P.R. China
| | - Kenan Zhang
- Department of Urology, Peking University First Hospital, Beijing 100034, P.R. China.,Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing 100034, P.R. China.,Institute of Urology, Peking University, Beijing 100034, P.R. China.,National Urological Cancer Center, Beijing 100034, P.R. China
| | - Kaifang Ma
- Department of Urology, Peking University First Hospital, Beijing 100034, P.R. China.,Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing 100034, P.R. China.,Institute of Urology, Peking University, Beijing 100034, P.R. China.,National Urological Cancer Center, Beijing 100034, P.R. China
| | - Yanqing Gong
- Department of Urology, Peking University First Hospital, Beijing 100034, P.R. China.,Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing 100034, P.R. China.,Institute of Urology, Peking University, Beijing 100034, P.R. China.,National Urological Cancer Center, Beijing 100034, P.R. China
| | - Jingcheng Zhou
- Department of Urology, Peking University First Hospital, Beijing 100034, P.R. China.,Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing 100034, P.R. China.,Institute of Urology, Peking University, Beijing 100034, P.R. China.,National Urological Cancer Center, Beijing 100034, P.R. China
| | - Kan Gong
- Department of Urology, Peking University First Hospital, Beijing 100034, P.R. China.,Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing 100034, P.R. China.,Institute of Urology, Peking University, Beijing 100034, P.R. China.,National Urological Cancer Center, Beijing 100034, P.R. China
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20
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Zhou YY, Chen LP, Zhang Y, Hu SK, Dong ZJ, Wu M, Chen QX, Zhuang ZZ, Du XJ. Integrated transcriptomic analysis reveals hub genes involved in diagnosis and prognosis of pancreatic cancer. Mol Med 2019; 25:47. [PMID: 31706267 PMCID: PMC6842480 DOI: 10.1186/s10020-019-0113-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 09/20/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The hunt for the molecular markers with specificity and sensitivity has been a hot area for the tumor treatment. Due to the poor diagnosis and prognosis of pancreatic cancer (PC), the excision rate is often low, which makes it more urgent to find the ideal tumor markers. METHODS Robust Rank Aggreg (RRA) methods was firstly applied to identify the differentially expressed genes (DEGs) between PC tissues and normal tissues from GSE28735, GSE15471, GSE16515, and GSE101448. Among these DEGs, the highly correlated genes were clustered using WGCNA analysis. The co-expression networks and molecular complex detection (MCODE) Cytoscape app were then performed to find the sub-clusters and confirm 35 candidate genes. For these genes, least absolute shrinkage and selection operator (lasso) regression model was applied and validated to build a diagnostic risk score model. Cox proportional hazard regression analysis was used and validated to build a prognostic model. RESULTS Based on integrated transcriptomic analysis, we identified a 19 gene module (SYCN, PNLIPRP1, CAP2, GNMT, MAT1A, ABAT, GPT2, ADHFE1, PHGDH, PSAT1, ERP27, PDIA2, MT1H, COMP, COL5A2, FN1, COL1A2, FAP and POSTN) as a specific predictive signature for the diagnosis of PC. Based on the two consideration, accuracy and feasibility, we simplified the diagnostic risk model as a four-gene model: 0.3034*log2(MAT1A)-0.1526*log2(MT1H) + 0.4645*log2(FN1) -0.2244*log2(FAP), log2(gene count). Besides, a four-hub gene module was also identified as prognostic model = - 1.400*log2(CEL) + 1.321*log2(CPA1) + 0.454*log2(POSTN) + 1.011*log2(PM20D1), log2(gene count). CONCLUSION Integrated transcriptomic analysis identifies two four-hub gene modules as specific predictive signatures for the diagnosis and prognosis of PC, which may bring new sight for the clinical practice of PC.
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Affiliation(s)
- Yang-Yang Zhou
- Department of Rheumatology and Immunology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province China
| | - Li-Ping Chen
- Department of Rheumatology and Immunology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province China
- Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325000 Zhejiang China
| | - Yi Zhang
- Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325000 Zhejiang China
| | - Sun-Kuan Hu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province China
| | - Zhao-Jun Dong
- Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325000 Zhejiang China
| | - Ming Wu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province China
| | - Qiu-Xiang Chen
- Department of Ultrasound, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province China
| | - Zhi-Zhi Zhuang
- Department of Rheumatology and Immunology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province China
| | - Xiao-Jing Du
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province China
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21
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Fleming AK, Storz P. Protein kinase C isoforms in the normal pancreas and in pancreatic disease. Cell Signal 2017; 40:1-9. [PMID: 28826907 DOI: 10.1016/j.cellsig.2017.08.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 08/17/2017] [Indexed: 12/16/2022]
Abstract
Protein Kinase C isoforms have been implicated in regulating multiple processes within the healthy pancreas. Moreover, their dysregulation contributes to all aspects of pancreatic disease. In this review, with a focus on acinar, ductal, and islet cells, we highlight the roles and contributions of the different PKC isoforms to normal pancreas function. We also discuss the contribution of PKC enzymes to pancreatic diseases, including insulin resistance and diabetes mellitus, as well as pancreatitis and the development and progression of pancreatic cancer.
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Affiliation(s)
- Alicia K Fleming
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
| | - Peter Storz
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
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22
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Takasawa K, Takasawa A, Osanai M, Aoyama T, Ono Y, Kono T, Hirohashi Y, Murata M, Sawada N. Claudin-18 coupled with EGFR/ERK signaling contributes to the malignant potentials of bile duct cancer. Cancer Lett 2017. [PMID: 28624624 DOI: 10.1016/j.canlet.2017.05.033] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Our recent work revealed that elevated expression of claudin-18 is involved in bile duct neoplasia. In the present study, we found that wound generation of a cell sheet de novo induced claudin-18 expression in its leading edge, coincident with high mitotic activity. We also found that the suppression of claudin-18 expression significantly reduced cell growth and invasiveness of bile duct cancer cell lines and tumorigenicity in vivo. In addition, an antibody specific to an extracellular loop of claudin-18 showed similar effects on the cells such as cell proliferation. Interestingly, treatment with epidermal growth factor (EGF) and overexpression of RAS oncogene induced claudin-18 expression by activation of extracellular signal-related kinase (ERK)1/2. Furthermore, enhanced claudin-18 expression activated ERK1/2. These findings provide evidence for an oncogenic property of claudin-18 in bile duct carcinoma cells via modulation of EGFR/ERK signaling, indicating that claudin-18 is a possible therapeutic target for this malignancy.
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Affiliation(s)
- Kumi Takasawa
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Akira Takasawa
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
| | - Makoto Osanai
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tomoyuki Aoyama
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yusuke Ono
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tsuyoshi Kono
- Department of Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yoshihiko Hirohashi
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masaki Murata
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Norimasa Sawada
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
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23
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Akizuki R, Shimobaba S, Matsunaga T, Endo S, Ikari A. Claudin-5, -7, and -18 suppress proliferation mediated by inhibition of phosphorylation of Akt in human lung squamous cell carcinoma. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1864:293-302. [PMID: 27884700 DOI: 10.1016/j.bbamcr.2016.11.018] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 10/26/2016] [Accepted: 11/18/2016] [Indexed: 12/11/2022]
Abstract
Abnormal expression of claudin (CLDN) subtypes has been reported in various solid cancers. However, it is unknown which subtype plays a key role in the regulation of proliferation in cancer cells. The expression of CLDN3-5, 7, and 18 in human lung squamous carcinoma tissues was lower than that in normal tissue. Here, we examined which combination of exogenous CLDNs expression inhibits proliferation and the molecular mechanism using human lung squamous RERF-LC-AI cells. Real-time polymerase chain reaction and western blotting showed that CLDN3-5, 7, and 18 are little expressed in RERF-LC-AI cells. In the exogenously transfected cells, CLDN5, 7, and 18 were distributed in the cell-cell contact areas concomitant with ZO-1, a tight junctional scaffolding protein, whereas CLDN3 and 4 were not. Cell proliferation was individually and additively suppressed by CLDN5, 7, and 18. The expression of these CLDNs showed no cytotoxicity compared with mock cells. CLDN5, 7, and 18 increased p21 and decreased cyclin D1, resulting in the suppression of cell cycle G1-S transition. The expression of these CLDNs inhibited phosphorylation of Akt without affecting phosphorylated ERK1/2. Furthermore, these CLDNs inhibited the nuclear localization of Akt and its association with 3-phosphoinositide-dependent protein kinase-1 (PDK1). The suppression of G1-S transition caused by CLDN5, 7, and 18 was rescued by the expression of constitutively active-Akt. We suggest that the reduction of CLDN5, 7, and 18 expression loses the suppressive ability of interaction between PDK1 and Akt and causes sustained phosphorylation of Akt, resulting in the disordered proliferation in lung squamous carcinoma cells.
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Affiliation(s)
- Risa Akizuki
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University
| | - Shun Shimobaba
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University
| | - Toshiyuki Matsunaga
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University
| | - Satoshi Endo
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University
| | - Akira Ikari
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University.
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24
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Osanai M, Takasawa A, Murata M, Sawada N. Claudins in cancer: bench to bedside. Pflugers Arch 2016; 469:55-67. [PMID: 27624415 DOI: 10.1007/s00424-016-1877-7] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 08/31/2016] [Accepted: 09/06/2016] [Indexed: 02/07/2023]
Abstract
The claudin family, in mammals, encoded by at least 27 members of a single ancestral gene, CLDN, is the main constituent as integral membrane proteins of tight junctions. It has been shown that the expression levels of claudins are often decreased or that their expressions are absent in human neoplasias. These findings are consistent with the well-accepted concept that carcinogenesis is accompanied by the disruption or loss of functional tight junctions. In contrast, accumulating data have showed elevated or aberrant expression of claudins in various cancers, indicating specific roles of claudins in tumorigenesis. Importantly, dysregulated claudins play an oncogenic role or conversely have a tumor-suppressive effect depending on target tissues or cell types, and thus, they contribute to tumor development and progression. Although tight junctions are intercellular structures in epithelial cells, specific roles of claudins in cancer are supported by the evidence that TJs are not simple static constituents for establishing cell adhesion structures but are also cell signaling components that have functions in receiving environmental cues and transmitting signals inside cells. Since the expression profile of claudins is associated with patients' outcome and prognosis in several cancer types, an understanding of the expression pattern and subcellular localization of claudins in various pathologies will lead to the establishment of claudins as useful biomarkers for the detection and diagnosis of cancers.
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Affiliation(s)
- Makoto Osanai
- Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556, Japan.
| | - Akira Takasawa
- Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Masaki Murata
- Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Norimasa Sawada
- Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556, Japan
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25
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Claudin-18 inhibits cell proliferation and motility mediated by inhibition of phosphorylation of PDK1 and Akt in human lung adenocarcinoma A549 cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1863:1170-8. [PMID: 26919807 DOI: 10.1016/j.bbamcr.2016.02.015] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Revised: 02/01/2016] [Accepted: 02/22/2016] [Indexed: 11/20/2022]
Abstract
Abnormal expression of claudin subtypes has been reported in various cancers. However, the pathological role of each claudin has not been clarified in detail. Claudin-18 was absent in human non-small cell and small cell lung cancers, although it is expressed in normal lung tissues. Here, we examined the effect of claudin-18 expression on the expression of junctional proteins, cell proliferation, and cell motility using human lung adenocarcinoma A549 cells. Real-time PCR and western blotting showed that exogenous expression of claudin-18 had no effect on the expression of junctional proteins including claudin-1, zonula occludens-1 (ZO-1), occludin, and E-cadherin. Claudin-18 was mainly distributed in cell-cell contact areas concomitant with ZO-1. Cell proliferation was significantly decreased at 48 and 72h after seeding of claudin 18-expressing cells. Claudin-18 suppressed cell motility, whereas it increased cell death in anoikis. Claudin-18 decreased phosphorylated (p)-3-phosphoinositide-dependent protein kinase-1 (PDK1) and p-Akt levels without affecting p-epidermal growth factor receptor and p-phosphatidylinositol-3 kinase (PI3K) levels. Furthermore, claudin-18 was bound with PDK1 and suppressed the nuclear localization of PDK1. We suggest that claudin-18 suppresses the abnormal proliferation and motility of lung epithelial cells mediated by inhibition of the PI3K/PDK1/Akt signaling pathway.
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26
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Singh R, Lillard JW, Singh S. Epigenetic Changes and Potential Targets in Pancreatic Cancer. EPIGENETIC ADVANCEMENTS IN CANCER 2016:27-63. [DOI: 10.1007/978-3-319-24951-3_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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27
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Kono T, Kondoh M, Kyuno D, Ito T, Kimura Y, Imamura M, Kohno T, Konno T, Furuhata T, Sawada N, Hirata K, Kojima T. Claudin-4 binder C-CPE 194 enhances effects of anticancer agents on pancreatic cancer cell lines via a MAPK pathway. Pharmacol Res Perspect 2015; 3:e00196. [PMID: 27022469 PMCID: PMC4777248 DOI: 10.1002/prp2.196] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Revised: 09/28/2015] [Accepted: 10/07/2015] [Indexed: 12/14/2022] Open
Abstract
The C‐terminal fragment of Clostridium perfringens enterotoxin (C‐CPE) modulates the tight junction protein claudin and disrupts the tight junctional barrier. It also can enhance the effectiveness of anticancer agents. However, the detailed mechanisms of the effects of C‐CPE remain unclear in both normal and cancerous cells. The C‐CPE mutant called C‐CPE 194 binds only to claudin‐4, but the C‐CPE 194 mutant called C‐CPE m19 binds not only to claudin‐4 but also to claudin‐1. In the present study, to investigate the mechanisms of the effects of C‐CPE on claudin expression, the tight junctional functions and the cytotoxicity of anticancer agents, human pancreatic cancer cells, and normal human pancreatic duct epithelial cells (HPDEs) were treated with C‐CPE 194 and C‐CPE m19. In well‐differentiated cells of the pancreatic cancer cell line HPAC, C‐CPE 194 and C‐CPE m19 disrupted both the barrier and fence functions without changes in expression of claudin‐1 and ‐4, together with an increase of MAPK phosphorylation. C‐CPE 194, but not C‐CPE m19, enhanced the cytotoxicity of the anticancer agents gemcitabine and S‐1. In poorly differentiated pancreatic cancer cell line PANC‐1, C‐CPE 194, but not C‐CPE m19, decreased claudin‐4 expression and enhanced MAPK activity and the cytotoxicity of the anticancer agents. In normal HPDEs, C‐CPE 194 and C‐CPE m19 decreased claudin‐4 expression and enhanced the MAPK activity, whereas they did not affect the cytotoxicity of the anticancer agents. Our findings suggest that the claudin‐4 binder C‐CPE 194 enhances effects of anticancer agents on pancreatic cancer cell lines via a MAPK pathway.
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Affiliation(s)
- Tsuyoshi Kono
- Department of Surgery Sapporo Medical University School of Medicine Sapporo Japan; Department of Cell Science Research Institute for Frontier Medicine Sapporo Medical University School of Medicine Sapporo Japan
| | - Masuo Kondoh
- Laboratory of Bio-Functional Molecular Chemistry Graduate School of Pharmaceutical Sciences Osaka University Suita Japan
| | - Daisuke Kyuno
- Department of Surgery Sapporo Medical University School of Medicine Sapporo Japan
| | - Tatsuya Ito
- Department of Surgery Sapporo Medical University School of Medicine Sapporo Japan
| | - Yasutoshi Kimura
- Department of Surgery Sapporo Medical University School of Medicine Sapporo Japan
| | - Masafumi Imamura
- Department of Surgery Sapporo Medical University School of Medicine Sapporo Japan
| | - Takayuki Kohno
- Department of Cell Science Research Institute for Frontier Medicine Sapporo Medical University School of Medicine Sapporo Japan
| | - Takumi Konno
- Department of Cell Science Research Institute for Frontier Medicine Sapporo Medical University School of Medicine Sapporo Japan
| | - Tomohisa Furuhata
- Department of Surgery Sapporo Medical University School of Medicine Sapporo Japan
| | - Norimasa Sawada
- Department of Pathology Sapporo Medical University School of Medicine Sapporo Japan
| | - Koichi Hirata
- Department of Surgery Sapporo Medical University School of Medicine Sapporo Japan
| | - Takashi Kojima
- Department of Cell Science Research Institute for Frontier Medicine Sapporo Medical University School of Medicine Sapporo Japan
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28
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Huang J, Zhang L, He C, Qu Y, Li J, Zhang J, Du T, Chen X, Yu Y, Liu B, Zhu Z. Claudin-1 enhances tumor proliferation and metastasis by regulating cell anoikis in gastric cancer. Oncotarget 2015; 6:1652-65. [PMID: 25544763 PMCID: PMC4359322 DOI: 10.18632/oncotarget.2936] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Accepted: 12/01/2014] [Indexed: 01/14/2023] Open
Abstract
Claudin-1 (CLDN1) is overexpressed in gastric cancer and correlated with tumor invasion, metastasis and poor outcome. Here, we both down and up regulated CLDN1 expression in gastric cancer cells to elucidate its role in gastric carcinogenesis and tumor progression. We found that deficiency of CLDN1 inhibited cells migration, invasion, and colony formation in vitro and tumorigenicity, metastasis in vivo. Also, CLDN1 promoted cell aggregation and increased anoikis resistance. Down or up regulation of CLDN1 was accompanied with changes of membrane β-catenin expression as well as Akt and Src activities. When β-catenin was up-regulated in CLDN1-KD cells, cell aggregation and anoikis resistance were restored, and Akt and Src signal pathways were re-activated. Taken together, these findings suggest that CLDN1 is oncogenic in gastric cancer and its malignant potential may be attributed in part to regulation of anoikis, by mediating membrane β-catenin-regulated cell-cell adhesion and cell survival.
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Affiliation(s)
- Jie Huang
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Zhang
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Changyu He
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying Qu
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianfang Li
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianian Zhang
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tao Du
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuehua Chen
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yingyan Yu
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bingya Liu
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenggang Zhu
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Ikari A, Fujii N, Hahakabe S, Hayashi H, Yamaguchi M, Yamazaki Y, Endo S, Matsunaga T, Sugatani J. Hyperosmolarity-Induced Down-Regulation of Claudin-2 Mediated by Decrease in PKCβ-Dependent GATA-2 in MDCK Cells. J Cell Physiol 2015; 230:2776-87. [PMID: 25825272 DOI: 10.1002/jcp.25004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 03/25/2015] [Indexed: 01/20/2023]
Abstract
Hyperosmolarity decreases claudin-2 expression in renal tubular epithelial cells, but the molecular mechanism remains undefined. Here, we found that the hyperosmolarity-induced decrease in claudin-2 expression is inhibited by Go6983, a non-selective protein kinase C (PKC) inhibitor, and PKCβ specific inhibitor in Madin-Darby canine kidney II cells. Hyperosmolarity increased intracellular free Ca(2+) concentration and phosphorylated PKCβ level, which were inhibited by RN-1734, an antagonist of transient receptor potential vanilloid 4 channel. Phorbol 12-myristate 13-acetate, a PKC activator, decreased claudin-2 expression. These results indicate hyperosmolarity decreases claudin-2 expression mediated by the activation of RN-1734-sensitive channel and PKCβ. Hyperosmolarity decreased promoter activity of claudin-2, which was inhibited by Go6983 and PKCβ inhibitor similar to those in real-time PCR and Western blotting. The effect of hyperosmolarity on promoter activity was not observed in the construct of -469/-6, a deletion mutant. Claudin-2 has hyperosmolarity-sensitive region in its promoter, which includes GATA binding site. Hyperosmolarity decreased the nuclear level of GATA-2, which was inhibited by Go6983 and PKCβ inhibitor. Mutation of GATA binding site decreased the basal promoter activity and inhibited the effect of hyperosmolarity. In contrast, the hyperosmolarity-induced decrease in reporter activity and claudin-2 expression were rescued by over-expression of wild type GATA-2. Chromatin immunoprecipitation assay showed that GATA-2 bound to promoter region of claudin-2. These results suggest that hyperosmolarity decreases the expression level of claudin-2 via a decrease in PKCβ-dependent GATA-2 transcriptional activity in renal tubular epithelial cells.
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Affiliation(s)
- Akira Ikari
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Japan
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Naoko Fujii
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Japan
| | - Shinya Hahakabe
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Hisayoshi Hayashi
- School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan
| | - Masahiko Yamaguchi
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Yasuhiro Yamazaki
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Satoshi Endo
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Japan
| | - Toshiyuki Matsunaga
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Japan
| | - Junko Sugatani
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
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30
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Claudins and cancer: Fall of the soldiers entrusted to protect the gate and keep the barrier intact. Semin Cell Dev Biol 2015; 42:58-65. [PMID: 26025580 DOI: 10.1016/j.semcdb.2015.05.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 05/04/2015] [Accepted: 05/06/2015] [Indexed: 12/11/2022]
Abstract
The role of the tight junctions (TJ) in controlling paracellular traffic of ions and molecules, through the regulation of claudin proteins, is now established. However, it has also become increasingly evident that claudin proteins, as integral components of the TJs, play crucial role in maintaining the cell-cell integrity. In conformity, deregulation of claudin expression and cellular distribution in cancer tissues has been widely documented and correlated with cancer progression and metastasis. However, this correlation is not unidirectional and rather suggests tissue specific regulations. Irrespective, if the widely described correlations between altered claudin expression and cancer initiation/progression could be established, they may serve as important markers for prognostic purposes and potential therapeutic targets. In this review, we summarize data from screening of the cancer tissues, manipulation of claudin expression in cells and animals subjected to cancer models, and how claudins are regulated in cancer. The focus of this article remains analysis of the association between cancer and the claudins and to decipher clinical relevance.
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31
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Keira Y, Takasawa A, Murata M, Nojima M, Takasawa K, Ogino J, Higashiura Y, Sasaki A, Kimura Y, Mizuguchi T, Tanaka S, Hirata K, Sawada N, Hasegawa T. An immunohistochemical marker panel including claudin-18, maspin, and p53 improves diagnostic accuracy of bile duct neoplasms in surgical and presurgical biopsy specimens. Virchows Arch 2015; 466:265-277. [PMID: 25503275 DOI: 10.1007/s00428-014-1705-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Revised: 10/06/2014] [Accepted: 12/02/2014] [Indexed: 12/14/2022]
Abstract
Biliary tract cancers have an extremely poor outcome, and specific diagnostic markers and effective treatments are needed urgently. In this study, we assessed the capacity of panel of immunohistochemical markers including claudin-18, maspin, and p53 to distinguish biliary tract carcinoma and biliary intraepithelial neoplasia (BilIN) from non-neoplastic epithelium. We performed a retrospective study of 66 biliary tract cancer specimens and 63 specimens with non-neoplastic lesions. Of the surgical specimens, 96.7 % with adenocarcinoma/BilIN were detected as neoplastic, and all 63 specimens histologically diagnosed as non-neoplastic lesion were detected as non-neoplastic with high sensitivity (91.1 %) and specificity (100 %). Of presurgical endobiliary forceps biopsy specimens, all with adenocarcinoma/BilIN and only 1 of the 19 with a non-neoplastic lesion were distinguished as neoplastic with high sensitivity (100 %) and specificity (94.7 %). Moreover, this panel provided good separation of neoplasm from malignancy-undetermined atypical epithelium (18/21, 85.7 %). This panel achieves a more reliable distinction of biliary tract cancers and BilINs from non-neoplastic epithelia in both surgical and biopsy specimens than immunohistochemical analysis with single antibodies and is useful in supporting a diagnosis of adenocarcinoma and BilIN.
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Affiliation(s)
- Yoshiko Keira
- Departments of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
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Kyuno D, Yamaguchi H, Ito T, Kono T, Kimura Y, Imamura M, Konno T, Hirata K, Sawada N, Kojima T. Targeting tight junctions during epithelial to mesenchymal transition in human pancreatic cancer. World J Gastroenterol 2014; 20:10813-10824. [PMID: 25152584 PMCID: PMC4138461 DOI: 10.3748/wjg.v20.i31.10813] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 05/05/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer continues to be a leading cause of cancer-related death worldwide and there is an urgent need to develop novel diagnostic and therapeutic strategies to reduce the mortality of patients with this disease. In pancreatic cancer, some tight junction proteins, including claudins, are abnormally regulated and therefore are promising molecular targets for diagnosis, prognosis and therapy. Claudin-4 and -18 are overexpressed in human pancreatic cancer and its precursor lesions. Claudin-4 is a high affinity receptor of Clostridium perfringens enterotoxin (CPE). The cytotoxic effects of CPE and monoclonal antibodies against claudin-4 are useful as novel therapeutic tools for pancreatic cancer. Claudin-18 could be a putative marker and therapeutic target with prognostic implications for patients with pancreatic cancer. Claudin-1, -7, tricellulin and marvelD3 are involved in epithelial to mesenchymal transition (EMT) of pancreatic cancer cells and thus might be useful as biomarkers during disease. Protein kinase C is closely related to EMT of pancreatic cancer and regulates tight junctions of normal human pancreatic duct epithelial cells and the cancer cells. This review focuses on the regulation of tight junctions via protein kinase C during EMT in human pancreatic cancer for the purpose of developing new diagnostic and therapeutic modalities for pancreatic cancer.
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Neureiter D, Jäger T, Ocker M, Kiesslich T. Epigenetics and pancreatic cancer: pathophysiology and novel treatment aspects. World J Gastroenterol 2014; 20:7830-7848. [PMID: 24976721 PMCID: PMC4069312 DOI: 10.3748/wjg.v20.i24.7830] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 02/07/2014] [Accepted: 03/12/2014] [Indexed: 02/06/2023] Open
Abstract
An improvement in pancreatic cancer treatment represents an urgent medical goal. Late diagnosis and high intrinsic resistance to conventional chemotherapy has led to a dismal overall prognosis that has remained unchanged during the past decades. Increasing knowledge about the molecular pathogenesis of the disease has shown that genetic alterations, such as mutations of K-ras, and especially epigenetic dysregulation of tumor-associated genes, such as silencing of the tumor suppressor p16(ink4a), are hallmarks of pancreatic cancer. Here, we describe genes that are commonly affected by epigenetic dysregulation in pancreatic cancer via DNA methylation, histone acetylation or miRNA (microRNA) expression, and review the implications on pancreatic cancer biology such as epithelial-mesenchymal transition, morphological pattern formation, or cancer stem cell regulation during carcinogenesis from PanIN (pancreatic intraepithelial lesions) to invasive cancer and resistance development. Epigenetic drugs, such as DNA methyltransferases or histone deactylase inhibitors, have shown promising preclinical results in pancreatic cancer and are currently in early phases of clinical development. Combinations of epigenetic drugs with established cytotoxic drugs or targeted therapies are promising approaches to improve the poor response and survival rate of pancreatic cancer patients.
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Feng W, Zhang B, Cai D, Zou X. Therapeutic potential of histone deacetylase inhibitors in pancreatic cancer. Cancer Lett 2014; 347:183-90. [PMID: 24534202 DOI: 10.1016/j.canlet.2014.02.012] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Revised: 01/22/2014] [Accepted: 02/10/2014] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer is a devastating disease with a dismal prognosis. Surgical resection is the only curative option but is heavily hampered by delayed diagnosis. Due to few therapeutic treatments available, novel and efficacious therapy is urgently needed. Histone deacetylase inhibitors (HDACIs) are emerging as a prominent class of therapeutic agents for pancreatic cancer and have exhibited significant anticancer potential with negligible toxicity in preclinical studies. Clinical evaluations of HDACIs are currently underway. HDACIs as monotherapy in solid tumors have proven less effective than hematological malignancies, the combination of HDACIs with other anticancer agents have been assessed for advanced pancreatic cancer. In this review, we describe the molecular mechanism underpin the anticancer effect of HDACIs in pancreatic cancer and summarize the recent advances in the rationale for the combination strategies incorporating HDACIs. In addition, we discuss the importance of identifying predictors of response to HDACI-based therapy.
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Affiliation(s)
- Wan Feng
- Department of Gastroenterology, The Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing 210008, PR China; Medical School of Nanjing University, Nanjing, PR China
| | - Bin Zhang
- Department of Gastroenterology, The Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing 210008, PR China
| | - Dawei Cai
- Medical School of Nanjing University, Nanjing, PR China
| | - Xiaoping Zou
- Department of Gastroenterology, The Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing 210008, PR China.
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Wöll S, Schlitter AM, Dhaene K, Roller M, Esposito I, Sahin U, Türeci Ö. Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms. Int J Cancer 2013; 134:731-9. [PMID: 23900716 DOI: 10.1002/ijc.28400] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Accepted: 07/09/2013] [Indexed: 12/15/2022]
Abstract
The majority of pancreatic neoplasms are characterized by a generally lethal progress within a short period of time after primary diagnosis and the mortality of patients is expected to increase further. Due to lack of efficient screening programs and moderate response to treatments, novel compounds for treatment are needed. We investigated the CLDN18.2 expression in affected patients as in vitro feasibility study for a potential treatment with the novel antibody IMAB362. Therefore, we analyzed the expression of CLDN18.2 in normal pancreatic tissues (N = 24), primary lesions (N = 202), metastases (N = 84) and intra-individually matched samples (N = 48) of patients with pancreatic ductal adenocarcinoma (PDAC), neuroendocrine neoplasia (NEN) and acinar cell carcinoma. A standardized method for evaluation by immunohistochemistry was developed. The specific staining was evaluated by two independent raters and analysis of staining intensities (range 0-3+) and relative proportions of tumor cells were performed. One hundred three (59.2%) samples of primary PDAC were found positive. The vast majority of positive samples were characterized to highly express CLDN18.2: 54.6% (N = 95) with staining intensities of ≥ 2+. NEN were positive in 20% of cases (all ≥ 2+). Metastases of pancreatic neoplasms were also frequently found positive with comparable high rates (69.4% of lymph node and 65.7% of liver metastases). The rate of CLDN18.2 positivity is high in pancreatic neoplasms whereby the expression is not limited to the primaries but is also maintained upon metastasis. Thus, a considerable number of patients with pancreatic neoplasms would be in principle eligible for a CLDN18.2-targeting approach.
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Kwon MJ. Emerging roles of claudins in human cancer. Int J Mol Sci 2013; 14:18148-80. [PMID: 24009024 PMCID: PMC3794774 DOI: 10.3390/ijms140918148] [Citation(s) in RCA: 159] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Revised: 08/23/2013] [Accepted: 08/27/2013] [Indexed: 02/07/2023] Open
Abstract
Claudins are major integral membrane proteins of tight junctions. Altered expression of several claudin proteins, in particular claudin-1, -3, -4 and -7, has been linked to the development of various cancers. Although their dysregulation in cancer suggests that claudins play a role in tumorigenesis, the exact underlying mechanism remains unclear. The involvement of claudins in tumor progression was suggested by their important role in the migration, invasion and metastasis of cancer cells in a tissue-dependent manner. Recent studies have shown that they play a role in epithelial to mesenchymal transition (EMT), the formation of cancer stem cells or tumor-initiating cells (CSCs/TICs), and chemoresistance, suggesting that claudins are promising targets for the treatment of chemoresistant and recurrent tumors. A recently identified claudin-low breast cancer subtype that is characterized by the enrichment of EMT and stem cell-like features is significantly associated with disease recurrence, underscoring the importance of claudins as predictors of tumor recurrence. The critical role of epigenetic mechanisms in the regulation of claudin expression indicates the possible application of epigenetic therapy to target claudins. A better understanding of the emerging role of claudins in CSC/TICs and chemoresistance may help to develop therapies against recurrent cancers.
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Affiliation(s)
- Mi Jeong Kwon
- College of Pharmacy, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 702-701, Korea.
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Lleras RA, Smith RV, Adrien LR, Schlecht NF, Burk RD, Harris TM, Childs G, Prystowsky MB, Belbin TJ. Unique DNA methylation loci distinguish anatomic site and HPV status in head and neck squamous cell carcinoma. Clin Cancer Res 2013; 19:5444-55. [PMID: 23894057 DOI: 10.1158/1078-0432.ccr-12-3280] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE We have used a genome-wide approach to identify novel differentially methylated CpG dinucleotides that are seen in different anatomic sites of head and neck squamous cell carcinoma (HNSCC), as well as those that might be related to HPV status in the oropharynx. EXPERIMENTAL DESIGN We conducted genome-wide DNA methylation profiling of primary tumor samples and corresponding adjacent mucosa from 118 HNSCC patients undergoing treatment at Montefiore Medical Center, Bronx, NY, using the Illumina HumanMethylation27 beadchip. For each matched tissue set, we measured differentially methylated CpG loci using a change in methylation level (M-value). RESULTS When datasets were individually analyzed by anatomic site of the primary tumor, we identified 293 differentially methylated CpG loci in oral cavity squamous cell carcinoma (SCC), 219 differentially methylated CpG loci in laryngeal SCC, and 460 differentially methylated in oropharyngeal SCC. A subset of these differentially methylated CpG loci was common across all anatomic sites of HNSCC. Stratification by HPV status revealed a significantly higher number of differentially methylated CpG loci in HPV+ patients. CONCLUSION Novel epigenetic biomarkers derived from clinical HNSCC specimens can be used as molecular classifiers of this disease, revealing many new avenues of investigation for this disease.
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Affiliation(s)
- Roberto A Lleras
- Authors' Affiliations: Departments of Pathology; Epidemiology & Population Health; Pediatrics, Microbiology & Immunology; Obstetrics, Gynecology & Women's Health, Albert Einstein College of Medicine; and Department of Otorhinolaryngology-Head and Neck Surgery, Montefiore Medical Center, Medical Arts Pavilion, Bronx, New York
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Kojima T, Yamaguchi H, Ito T, Kyuno D, Kono T, Konno T, Sawada N. Tight junctions in human pancreatic duct epithelial cells. Tissue Barriers 2013; 1:e24894. [PMID: 24665406 PMCID: PMC3805649 DOI: 10.4161/tisb.24894] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2013] [Revised: 04/28/2013] [Accepted: 05/01/2013] [Indexed: 12/13/2022] Open
Abstract
Tight junctions of the pancreatic duct are essential regulators of physiologic secretion of the pancreas and disruption of the pancreatic ductal barrier is known to contribute to the pathogenesis of pancreatitis and progression of pancreatic cancer. Various inflammatory mediators and carcinogens can trigger tight junction disassembly and disruption of the pancreatic barrier, however signaling events that mediates such barrier dysfunctions remain poorly understood. This review focuses on structure and regulation of tight junctions in normal pancreatic epithelial cells and mechanisms of junctional disruption during pancreatic inflammation and cancer. We will pay special attention to a novel model of human telomerase reverse transcriptase-transfected human pancreatic ductal epithelial cells and will describe the roles of major signaling molecules such as protein kinase C and c-Jun N-terminal kinase in formation and disassembly of the pancreatic ductal barrier.
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Affiliation(s)
- Takashi Kojima
- Department of Pathology; Sapporo Medical University School of Medicine; Sapporo, Japan ; Department of Cell Science; Research Institute of Frontier Medicine; Sapporo Medical University School of Medicine; Sapporo, Japan
| | - Hiroshi Yamaguchi
- Department of Surgery; Sapporo Medical University School of Medicine; Sapporo, Japan
| | - Tatsuya Ito
- Department of Surgery; Sapporo Medical University School of Medicine; Sapporo, Japan
| | - Daisuke Kyuno
- Department of Surgery; Sapporo Medical University School of Medicine; Sapporo, Japan
| | - Tsuyoshi Kono
- Department of Pathology; Sapporo Medical University School of Medicine; Sapporo, Japan ; Department of Surgery; Sapporo Medical University School of Medicine; Sapporo, Japan
| | - Takumi Konno
- Department of Pathology; Sapporo Medical University School of Medicine; Sapporo, Japan ; Department of Cell Science; Research Institute of Frontier Medicine; Sapporo Medical University School of Medicine; Sapporo, Japan
| | - Norimasa Sawada
- Department of Pathology; Sapporo Medical University School of Medicine; Sapporo, Japan
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Kyuno D, Kojima T, Yamaguchi H, Ito T, Kimura Y, Imamura M, Takasawa A, Murata M, Tanaka S, Hirata K, Sawada N. Protein kinase Cα inhibitor protects against downregulation of claudin-1 during epithelial-mesenchymal transition of pancreatic cancer. Carcinogenesis 2013; 34:1232-43. [PMID: 23389293 DOI: 10.1093/carcin/bgt057] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Protein kinase Cα (PKCα) is highly expressed in pancreatic cancer. However, the effects of PKCα on Snail and claudin-1, which play crucial roles in epithelial cell polarity during epithelial-mesenchymal transition (EMT), remain unclear. In this study, we investigated the mechanisms of regulation of Snail and claudin-1 via a PKCα signal pathway during EMT in pancreatic cancer cells and in normal human pancreatic duct epithelial cells (HPDEs). By immunostaining, overexpression of PKCα and downregulation of claudin-1 were observed in poorly differentiated human pancreatic cancer tissues and the pancreatic cancer cell line PANC-1. Treatment with the PKCα inhibitor Gö6976 transcriptionally decreased Snail and increased claudin-1 in PANC-1 cells. The PKCα inhibitor prevented upregulation of Snail and downregulation of claudin-1 during EMT induced by transforming growth factor-β1 (TGF-β1) treatment and under hypoxia in PANC-1 cells. The effects of the PKCα inhibitor were in part regulated via an extracellular signal-regulated kinase (ERK) signaling pathway. The PKCα inhibitor also prevented downregulation of the barrier function and fence function during EMT in well-differentiated pancreatic cancer cell line HPAC. In normal HPDEs, the PKCα inhibitor transcriptionally induced not only claudin-1 but also claudin-4, -7 and occludin without a change of Snail. Treatment with the PKCα inhibitor in normal HPDEs prevented downregulation of claudin-1 and occludin by TGF-β1 treatment and enhanced upregulation of claudin-1, -4, -7 and occludin under hypoxia. These findings suggest that PKCα regulates claudin-1 via Snail- and mitogen-activated protein kinase/ERK-dependent pathways during EMT in pancreatic cancer. Thus, PKCα inhibitors may be potential therapeutic agents against the malignancy of human pancreatic cancer cells.
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Affiliation(s)
- Daisuke Kyuno
- Department of Surgery, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
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Kojima T, Sawada N. Regulation of tight junctions in human normal pancreatic duct epithelial cells and cancer cells. Ann N Y Acad Sci 2012; 1257:85-92. [PMID: 22671593 DOI: 10.1111/j.1749-6632.2012.06579.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
To investigate the regulation of tight junction molecules in normal human pancreatic duct epithelial (HPDE) cells and pancreatic cancer cells, we introduced the human telomerase reverse transcriptase (hTERT) gene into HPDE cells in primary culture and compared them to pancreatic cancer cell lines. The hTERT-transfected HPDE cells were positive for PDE markers and expressed claudin-1, claudin-4, claudin-7, and claudin-18, occludin, tricellulin, marvelD3, JAM-A, zonula occludens (ZO)-1, and ZO-2. The tight junction molecules, including claudin-4 and claudin-18 of normal HPDE cells, were in part regulated via a protein kinase C signal pathway by transcriptional control. In addition, claudin-18 in normal HPDE cells and pancreatic cancer cells was markedly induced by a PKC activator, and claudin-18 in pancreatic cancer cells was also modified by DNA methylation. In the marvel family of normal HPDE cells and pancreatic cancer cells, tricellulin was upregulated via a c-Jun N-terminal kinase pathway, and marvelD3 was downregulated during Snail-induced epithelial-mesenchymal transition.
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Affiliation(s)
- Takashi Kojima
- Department of Pathology, Sapporo Medical University School of Medicine, Japan.
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Abstract
INTRODUCTION Pancreatic cancer is one of the most malignant human diseases and there is an urgent need to develop novel diagnostic and therapeutic strategies. Claudin-4, overexpressed in pancreatic cancer and its precursor lesions, is a receptor for Clostridium perfringens enterotoxin (CPE). The cytotoxic effects of CPE and monoclonal antibodies against claudin-4 are useful as novel therapeutic tools for pancreatic cancer. AREAS COVERED This review describes and discusses the studies targeting claudin-4 in normal human pancreatic duct epithelial (HPDE) cells and cancer cells. EXPERT OPINION Claudin-4 is in part regulated via a PKCα signal transduction pathway in pancreatic cancer cell lines. PKCα inhibitors may represent potential therapeutic agents against human pancreatic cancer cells by the use of CPE cytotoxicity via claudin-4. The COOH-terminal half fragment of CPE (C-CPE) enhances the effectiveness of clinically relevant chemotherapies and can be used as a carrier for drugs and other bacterial toxins to claudin-4-positive cancer cells. hTERT-HPDE cells, in which the human telomerase reverse transcriptase (hTERT) gene is introduced into normal HPDE cells, may be a useful model of normal HPDE cells not only for physiological regulation of claudin-4 expression but also for developing safer and more effective therapeutic methods targeting claudin-4 in pancreatic cancer.
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Affiliation(s)
- Takashi Kojima
- Sapporo Medical University School of Medicine, Department of Pathology, Sapporo, Japan.
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Claudin-5 is involved in breast cancer cell motility through the N-WASP and ROCK signalling pathways. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2012; 31:43. [PMID: 22559840 PMCID: PMC3432004 DOI: 10.1186/1756-9966-31-43] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2012] [Accepted: 02/18/2012] [Indexed: 01/02/2023]
Abstract
BACKGROUND Recent studies have shown dysregulation in TJ structure of several cancers including breast. Claudin-5 is a protein member of the TJ structure expressed in both endothelial and epithelial cells. This study examined the level of expression and distribution of Claudin-5 in human breast cancer tissues and the effect of knockdown and forced expression of Claudin-5 in the MDA-MB-231 breast cancer cell line. METHODS Immunohistochemistry and quantitative-PCR were used to analyse patient tissue samples. The Claudin-5 gene was cloned and overexpressed or knocked down using ribozyme technology in human breast cancer cells. Changes in function were assessed using in vitro assays for invasion, growth, adhesion, wounding, motility, transepithelial resistance and electric cell-substrate impedance sensing. Changes in cell behaviour were achieved through the use of Hepatocyte Growth factor (HGF) which we have shown to affect TJ function and expression of TJ proteins. In addition, an in vivo model was used for tumour growth assays. Results data was analyzed using a Students two sample t-test and by Two-way Anova test when the data was found to be normalized and have equal variances. In all cases 95% confidence intervals were used. RESULTS Patients whose tumours expressed high levels of Claudin-5 had shorter survival than those with low levels (p = 0.004). Investigating in vitro the effect of altering levels of expression of Claudin-5 in MDA-MB-231 cells revealed that the insertion of Claudin-5 gene resulted in significantly more motile cells (p < 0.005). Low levels of Claudin-5 resulted in a decrease in adhesion to matrix (p < 0.001). Furthermore, a possible link between Claudin-5 and N-WASP, and Claudin-5 and ROCK was demonstrated when interactions between these proteins were seen in the cells. Moreover, followed by treatment of N-WASP inhibitor (Wiskostatin) and ROCK inhibitor (Y-27632) cell motility was assessed in response to the inhibitors. Results showed that the knockdown of Claudin-5 in MDA-MB-231 masked their response after treatment with N-WASP inhibitor; however treatment with ROCK inhibitor did not reveal any differences in motility in this cell line. CONCLUSIONS This study portrays a very new and interesting role for Claudin-5 in cell motility involving the N-WASP signalling cascade indicating a possible role for Claudin-5 in the metastasis of human breast cancer.
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Protein kinase Cα inhibitor enhances the sensitivity of human pancreatic cancer HPAC cells to Clostridium perfringens enterotoxin via claudin-4. Cell Tissue Res 2011; 346:369-81. [PMID: 22160590 DOI: 10.1007/s00441-011-1287-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2011] [Accepted: 11/09/2011] [Indexed: 12/19/2022]
Abstract
Protein kinase C (PKC) is overexpressed in cancer, including pancreatic cancer, compared with normal tissue. Moreover, PKCα is considered one of the biomarkers for the diagnosis of cancers. In several human cancers, the claudin tight junction molecules are abnormally regulated and are thus promising molecular targets for diagnosis and therapy with Clostridium perfringens enterotoxin (CPE). In order to investigate the changes of tight junction functions of claudins via PKCα activation in pancreatic cancer cells, the well-differentiated human pancreatic cancer cell line HPAC, with its highly expressed tight junction molecules and well-developed barrier function, was treated with the PKC activator 12-O-tetradecanoylphorbol 13-acetate (TPA). Treatment with TPA modified the activity of phosphoPKCα and caused an increase of the Snail family members Snail, Slug and Smad-interacting protein 1 and a decrease of E-cadherin. In HPAC cells treated with TPA, downregulation of claudin-1 and mislocalization of claudin-4 and occludin around the nuclei were observed, together with a decrease in the numbers of tight junction strands and an increase in phosphorylation of claudin-4. The barrier function and the cytotoxicity of CPE were significantly decreased on TPA treatment. All such changes after TPA treatment were prevented by inhibitors of panPKC and PKCα. These findings suggest that, in human pancreatic cancer cells, PKCα activation downregulates tight junction functions as a barrier and as a receptor of CPE via the modification of claudin-1 and -4 during epithelial to mesenchymal transition-like changes. PKCα inhibitors might represent potential therapeutic agents against human pancreatic cancer cells by use of CPE cytotoxicity via claudin-4.
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