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Shen Y, Ma C, Li X, Li X, Wu Y, Yang T, Hu Y, Liu C, Shen H, Guo P, Shen Y. Generation of B7-H3 isoform regulated by ANXA2/NSUN2/YBX1 axis in human glioma. J Cell Mol Med 2024; 28:e18575. [PMID: 39048916 PMCID: PMC11269050 DOI: 10.1111/jcmm.18575] [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: 04/07/2024] [Revised: 07/01/2024] [Accepted: 07/18/2024] [Indexed: 07/27/2024] Open
Abstract
In recent years, in the development of emerging immunotherapy, B7-H3 is also termed as CD276 and has become a novel chimeric antigen receptor (CAR)-T target against glioma and other tumours, and aroused extensive attention. However, B7-H3 has three isoforms (2, 3 and 4Ig) with the controversial expression and elusive function in tumour especially glioma. The current study mainly focuses on the regulatory factors and related mechanisms of generation of different B7-H3 isoforms. First, we have determined that 2Ig is dominant in glioma with high malignancy, and 4Ig is widely expressed, whereas 3Ig shows negative expression in all glioma. Next, we have further found that RNA binding protein annexin A2 (ANXA2) is essential for B7-H3 isoform maintenance, but fail to determine the choice of 4Ig or 2Ig. RNA methyltransferase NOP2/Sun RNA methyltransferase 2 (NSUN2) and 5-methylcytosine reader Y-box binding protein 1 (YBX1) facilitate the production of 2Ig. Our findings have uncovered a series of factors (ANXA2/NSUN2/YBX1) that can determine the alternative generation of different isoforms of B7-H3 in glioma. Our result aims to help peers gain a clearer understanding of the expression and regulatory mechanisms of B7H3 in tumour patients, and to provide better strategies for designing B7H3 as a target in immunotherapy.
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Affiliation(s)
- Yifen Shen
- Central Laboratory, Suzhou Bay Clinical CollegeXuzhou Medical University, Suzhou Ninth People's HospitalSuzhouJiangsuChina
| | - Chunfang Ma
- Clinical LaboratorySuzhou Ninth People's HospitalSuzhouJiangsuChina
| | - Xiangxiang Li
- Clinical LaboratorySuzhou Ninth People's HospitalSuzhouJiangsuChina
| | - Xiaosong Li
- Department of Anorectal SurgerySuzhou Ninth People's HospitalSuzhouJiangsuChina
| | - Yuxiang Wu
- Department of PathologySuzhou Ninth People's HospitalSuzhouJiangsuChina
| | - Tao Yang
- Department of Medical Cosmetology, Suzhou Ninth People's HospitalSoochow UniversitySuzhouJiangsuChina
| | - Yanping Hu
- Department of Molecular PathologyThe Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer HospitalZhengzhouHenanChina
| | - Chao Liu
- Central Laboratory, Suzhou Bay Clinical CollegeXuzhou Medical University, Suzhou Ninth People's HospitalSuzhouJiangsuChina
| | - Hao Shen
- Clinical LaboratorySuzhou Ninth People's HospitalSuzhouJiangsuChina
| | - Pin Guo
- Department of NeurosurgeryThe Affiliated Hospital of Qingdao UniversityQingdaoShandongChina
| | - Yihang Shen
- Central Laboratory, Suzhou Bay Clinical CollegeXuzhou Medical University, Suzhou Ninth People's HospitalSuzhouJiangsuChina
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Ostrowska-Lesko M, Rajtak A, Moreno-Bueno G, Bobinski M. Scientific and clinical relevance of non-cellular tumor microenvironment components in ovarian cancer chemotherapy resistance. Biochim Biophys Acta Rev Cancer 2024; 1879:189036. [PMID: 38042260 DOI: 10.1016/j.bbcan.2023.189036] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 11/24/2023] [Accepted: 11/25/2023] [Indexed: 12/04/2023]
Abstract
The tumor microenvironment (TME) components play a crucial role in cancer cells' resistance to chemotherapeutic agents. This phenomenon is exceptionally fundamental in patients with ovarian cancer (OvCa), whose outcome depends mainly on their response to chemotherapy. Until now, most reports have focused on the role of cellular components of the TME, while less attention has been paid to the stroma and other non-cellular elements of the TME, which may play an essential role in the therapy resistance. Inhibiting these components could help define new therapeutic targets and potentially restore chemosensitivity. The aim of the present article is both to summarize the knowledge about non-cellular components of the TME in the development of OvCa chemoresistance and to suggest targeting of non-cellular elements of the TME as a valuable strategy to overcome chemoresistance and to develop new therapeutic strategies in OvCA patients.
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Affiliation(s)
- Marta Ostrowska-Lesko
- Chair and Department of Toxicology, Medical University of Lublin, 8b Jaczewskiego Street, 20-090 Lublin, Poland.
| | - Alicja Rajtak
- 1st Chair and Department of Oncological Gynecology and Gynecology, Medical University of Lublin, Poland
| | - Gema Moreno-Bueno
- Biochemistry Department, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas 'Sols-Morreale' (IIBm-CISC), Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Spain; Fundación MD Anderson Internacional (FMDA), Spain.
| | - Marcin Bobinski
- 1st Chair and Department of Oncological Gynecology and Gynecology, Medical University of Lublin, Poland.
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Elkady N, Aldesoky AI, Allam DM. Can β-catenin, Tenascin and Fascin be potential biomarkers for personalized therapy in Gastric carcinoma? J Immunoassay Immunochem 2023; 44:396-417. [PMID: 37694977 DOI: 10.1080/15321819.2023.2251564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
Gastric carcinoma (GC) is one of the most prevalent cancers worldwide and the fourth leading cause of cancer-related death. Studying the molecular profile of GC is essential for developing targeted therapies. β-catenin, Tenascin, and Fascin expression are among the molecular abnormalities that are claimed to cause GC progression and chemoresistance. Therefore, they could be used as potential therapeutic targets. This study aimed to evaluate β-catenin, Tenascin, and Fascin expression and their possible roles as prognostic and predictive biomarkers in GC using immunohistochemistry. This retrospective study included 84 GC cases. Tissue microarrays were constructed, followed by β-catenin, Tenascin, and Fascin immunostaining. Their expression was assessed and compared with clinicopathological parameters and survival data. The study results revealed that β-catenin nucleocytoplasmic expression, positive Tenascin, and Fascin expressions were detected in 86.9%, 70%, and 59.5% of cases, respectively. Their expression was significantly associated with poor prognostic parameters, such as deeper tumor invasion, lymph node metastasis, advanced pathological stage, vascular invasion, positive omental nodules, poor response to chemotherapy, and short overall survival. Hence, nucleocytoplasmic β-catenin expression together with Tenascin and Fascin positivity can be potential prognostic and predictive markers, and they can be used as therapeutic targets for GC.
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Affiliation(s)
- Noha Elkady
- Pathology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | - Amira I Aldesoky
- Clinical oncology and nuclear medicine department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | - Dina Mohamed Allam
- Pathology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
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4
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Lin L, Hu K. Annexin A2 and Kidney Diseases. Front Cell Dev Biol 2022; 10:974381. [PMID: 36120574 PMCID: PMC9478026 DOI: 10.3389/fcell.2022.974381] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/08/2022] [Indexed: 11/22/2022] Open
Abstract
Annexin A2 is a Ca2+- and phospholipid-binding protein which is widely expressed in various types of cells and tissues. As a multifunctional molecule, annexin A2 is found to be involved in diverse cell functions and processes, such as cell exocytosis, endocytosis, migration and proliferation. As a receptor of plasminogen and tissue plasminogen activator, annexin A2 promotes plasmin generation and regulates the homeostasis of blood coagulation, fibrinolysis and matrix degradation. As an antigen expressed on cell membranes, annexin A2 initiates local inflammation and damage through binding to auto-antibodies. Annexin A2 also mediates multiple signaling pathways induced by various growth factors and oxidative stress. Aberrant expression of annexin A2 has been found in numerous kidney diseases. Annexin A2 has been shown to act as a co-receptor of integrin CD11b mediating NF-kB-dependent kidney inflammation, which is further amplified through annexin A2/NF-kB-triggered macrophage M2 to M1 phenotypic change. It also modulates podocyte cytoskeleton rearrangement through Cdc42 and Rac1/2/3 Rho pathway causing proteinuria. Thus, annexin A2 is implicated in the pathogenesis and progression of various kidney diseases. In this review, we focus on the current understanding of the role of annexin A2 in kidney diseases.
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Affiliation(s)
- Ling Lin
- *Correspondence: Ling Lin, ; Kebin Hu,
| | - Kebin Hu
- *Correspondence: Ling Lin, ; Kebin Hu,
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5
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Tucker RP, Degen M. Revisiting the Tenascins: Exploitable as Cancer Targets? Front Oncol 2022; 12:908247. [PMID: 35785162 PMCID: PMC9248440 DOI: 10.3389/fonc.2022.908247] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 05/16/2022] [Indexed: 12/12/2022] Open
Abstract
For their full manifestation, tumors require support from the surrounding tumor microenvironment (TME), which includes a specific extracellular matrix (ECM), vasculature, and a variety of non-malignant host cells. Together, these components form a tumor-permissive niche that significantly differs from physiological conditions. While the TME helps to promote tumor progression, its special composition also provides potential targets for anti-cancer therapy. Targeting tumor-specific ECM molecules and stromal cells or disrupting aberrant mesenchyme-cancer communications might normalize the TME and improve cancer treatment outcome. The tenascins are a family of large, multifunctional extracellular glycoproteins consisting of four members. Although each have been described to be expressed in the ECM surrounding cancer cells, tenascin-C and tenascin-W are currently the most promising candidates for exploitability and clinical use as they are highly expressed in various tumor stroma with relatively low abundance in healthy tissues. Here, we review what is known about expression of all four tenascin family members in tumors, followed by a more thorough discussion on tenascin-C and tenascin-W focusing on their oncogenic functions and their potential as diagnostic and/or targetable molecules for anti-cancer treatment purposes.
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Affiliation(s)
- Richard P. Tucker
- Department of Cell Biology and Human Anatomy, University of California, Davis, Davis, CA, United States
| | - Martin Degen
- Laboratory for Oral Molecular Biology, Department of Orthodontics and Dentofacial Orthopedics, University of Bern, Bern, Switzerland
- *Correspondence: Martin Degen,
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Koltai T, Reshkin SJ, Carvalho TMA, Di Molfetta D, Greco MR, Alfarouk KO, Cardone RA. Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma: A Physiopathologic and Pharmacologic Review. Cancers (Basel) 2022; 14:2486. [PMID: 35626089 PMCID: PMC9139729 DOI: 10.3390/cancers14102486] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a poor prognosis and inadequate response to treatment. Many factors contribute to this therapeutic failure: lack of symptoms until the tumor reaches an advanced stage, leading to late diagnosis; early lymphatic and hematic spread; advanced age of patients; important development of a pro-tumoral and hyperfibrotic stroma; high genetic and metabolic heterogeneity; poor vascular supply; a highly acidic matrix; extreme hypoxia; and early development of resistance to the available therapeutic options. In most cases, the disease is silent for a long time, andwhen it does become symptomatic, it is too late for ablative surgery; this is one of the major reasons explaining the short survival associated with the disease. Even when surgery is possible, relapsesare frequent, andthe causes of this devastating picture are the low efficacy ofand early resistance to all known chemotherapeutic treatments. Thus, it is imperative to analyze the roots of this resistance in order to improve the benefits of therapy. PDAC chemoresistance is the final product of different, but to some extent, interconnected factors. Surgery, being the most adequate treatment for pancreatic cancer and the only one that in a few selected cases can achieve longer survival, is only possible in less than 20% of patients. Thus, the treatment burden relies on chemotherapy in mostcases. While the FOLFIRINOX scheme has a slightly longer overall survival, it also produces many more adverse eventsso that gemcitabine is still considered the first choice for treatment, especially in combination with other compounds/agents. This review discusses the multiple causes of gemcitabine resistance in PDAC.
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Affiliation(s)
| | - Stephan Joel Reshkin
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Tiago M. A. Carvalho
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Daria Di Molfetta
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Khalid Omer Alfarouk
- Zamzam Research Center, Zamzam University College, Khartoum 11123, Sudan;
- Alfarouk Biomedical Research LLC, Temple Terrace, FL 33617, USA
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
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Huang Y, Jia M, Yang X, Han H, Hou G, Bi L, Yang Y, Zhang R, Zhao X, Peng C, Ouyang X. Annexin A2: The Diversity of Pathological Effects in Tumorigenesis and Immune Response. Int J Cancer 2022; 151:497-509. [PMID: 35474212 DOI: 10.1002/ijc.34048] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 04/12/2022] [Accepted: 04/14/2022] [Indexed: 11/11/2022]
Abstract
Annexin A2 (ANXA2) is widely used as a marker in a variety of tumors. By regulating multiple signal pathways, ANXA2 promotes the epithelial-mesenchymal transition, which can cause tumorigenesis and accelerate thymus degeneration. The elevated ANXA2 heterotetramer facilitates the production of plasmin, which participates in pathophysiologic processes such as tumor cell invasion and metastasis, bleeding diseases, angiogenesis, inducing the expression of inflammatory factors. In addition, the ANXA2 on the cell membrane mediates immune response via its interaction with surface proteins of pathogens, C1q, toll-like receptor 2, anti-dsDNA antibodies and immunoglobulins. Nuclear ANXA2 plays a role as part of a primer recognition protein complex that enhances DNA synthesis and cells proliferation by acting on the G1-S phase of the cell. ANXA2 reduction leads to the inhibition of invasion and metastasis in multiple tumor cells, bleeding complications in acute promyelocytic leukemia, retinal angiogenesis, autoimmunity response and tumor drug resistance. In this review, we provide an update on the pathological effects of ANXA2 in both tumorigenesis and the immune response. We highlight ANXA2 as a critical protein in numerous malignancies and the immune host response.
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Affiliation(s)
- Yanjie Huang
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China.,Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Henan, China
| | - Mengzhen Jia
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Xiaoqing Yang
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Henan, China
| | - Hongyan Han
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Gailing Hou
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Liangliang Bi
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Henan, China
| | - Yueli Yang
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Henan, China
| | - Ruoqi Zhang
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Xueru Zhao
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Chaoqun Peng
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Xinshou Ouyang
- Department of Internal Medicine, Digestive Disease Section, Yale University, New Haven, Ct, USA
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8
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Gopinath P, Natarajan A, Sathyanarayanan A, Veluswami S, Gopisetty G. The multifaceted role of Matricellular Proteins in health and cancer, as biomarkers and therapeutic targets. Gene 2022; 815:146137. [PMID: 35007686 DOI: 10.1016/j.gene.2021.146137] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 12/07/2021] [Accepted: 12/20/2021] [Indexed: 02/07/2023]
Abstract
The extracellular matrix (ECM) is composed of a mesh of proteins, proteoglycans, growth factors, and other secretory components. It constitutes the tumor microenvironment along with the endothelial cells, cancer-associated fibroblasts, adipocytes, and immune cells. The proteins of ECM can be functionally classified as adhesive proteins and matricellular proteins (MCP). In the tumor milieu, the ECM plays a major role in tumorigenesis and therapeutic resistance. The current review encompasses thrombospondins, osteonectin, osteopontin, tenascin C, periostin, the CCN family, laminin, biglycan, decorin, mimecan, and galectins. The matrix metalloproteinases (MMPs) are also discussed as they are an integral part of the ECM with versatile functions in the tumor stroma. In this review, the role of these proteins in tumor initiation, growth, invasion and metastasis have been highlighted, with emphasis on their contribution to tumor therapeutic resistance. Further, their potential as biomarkers and therapeutic targets based on existing evidence are discussed. Owing to the recent advancements in protein targeting, the possibility of agents to modulate MCPs in cancer as therapeutic options are discussed.
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Affiliation(s)
- Prarthana Gopinath
- Department of Molecular Oncology, Cancer Institute WIA, Chennai, Tamil Nadu, India
| | - Aparna Natarajan
- Department of Molecular Oncology, Cancer Institute WIA, Chennai, Tamil Nadu, India
| | | | - Sridevi Veluswami
- Deaprtment of Surgical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
| | - Gopal Gopisetty
- Department of Molecular Oncology, Cancer Institute WIA, Chennai, Tamil Nadu, India.
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Geleta B, Tout FS, Lim SC, Sahni S, Jansson PJ, Apte MV, Richardson DR, Kovačević Ž. Targeting Wnt/tenascin C-mediated cross talk between pancreatic cancer cells and stellate cells via activation of the metastasis suppressor NDRG1. J Biol Chem 2022; 298:101608. [PMID: 35065073 PMCID: PMC8881656 DOI: 10.1016/j.jbc.2022.101608] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 01/02/2022] [Accepted: 01/05/2022] [Indexed: 02/06/2023] Open
Abstract
A major barrier to successful pancreatic cancer (PC) treatment is the surrounding stroma, which secretes growth factors/cytokines that promote PC progression. Wnt and tenascin C (TnC) are key ligands secreted by stromal pancreatic stellate cells (PSCs) that then act on PC cells in a paracrine manner to activate the oncogenic β-catenin and YAP/TAZ signaling pathways. Therefore, therapies targeting oncogenic Wnt/TnC cross talk between PC cells and PSCs constitute a promising new therapeutic approach for PC treatment. The metastasis suppressor N-myc downstream-regulated gene-1 (NDRG1) inhibits tumor progression and metastasis in numerous cancers, including PC. We demonstrate herein that targeting NDRG1 using the clinically trialed anticancer agent di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) inhibited Wnt/TnC-mediated interactions between PC cells and the surrounding PSCs. Mechanistically, NDRG1 and DpC markedly inhibit secretion of Wnt3a and TnC by PSCs, while also attenuating Wnt/β-catenin and YAP/TAZ activation and downstream signaling in PC cells. This antioncogenic activity was mediated by direct inhibition of β-catenin and YAP/TAZ nuclear localization and by increasing the Wnt inhibitor, DKK1. Expression of NDRG1 also inhibited transforming growth factor (TGF)-β secretion by PC cells, a key mechanism by which PC cells activate PSCs. Using an in vivo orthotopic PC mouse model, we show DpC downregulated β-catenin, TnC, and YAP/TAZ, while potently increasing NDRG1 expression in PC tumors. We conclude that NDRG1 and DpC inhibit Wnt/TnC-mediated interactions between PC cells and PSCs. These results further illuminate the antioncogenic mechanism of NDRG1 and the potential of targeting this metastasis suppressor to overcome the oncogenic effects of the PC-PSC interaction.
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Affiliation(s)
- Bekesho Geleta
- Cancer Metastasis and Tumor Microenvironment Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia
| | - Faten S Tout
- Cancer Metastasis and Tumor Microenvironment Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Department of Medical Laboratory Science, Faculty of Allied Health Sciences, The Hashemite University, Zarqa, Jordan
| | - Syer Choon Lim
- Cancer Metastasis and Tumor Microenvironment Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia
| | - Sumit Sahni
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia
| | - Patric J Jansson
- Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia; Cancer Drug Resistance & Stem Cell Program, Faculty of Medicine and Health, School of Medical Science, University of Sydney, Sydney, New South Wales, Australia
| | - Minoti V Apte
- Pancreatic Research Group, South Western Sydney Clinical School, UNSW Sydney, Sydney, New South Wales, Australia; Pancreatic Research Group, Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia
| | - Des R Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Žaklina Kovačević
- Cancer Metastasis and Tumor Microenvironment Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia.
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Giblin SP, Schwenzer A, Midwood KS. Alternative splicing controls cell lineage-specific responses to endogenous innate immune triggers within the extracellular matrix. Matrix Biol 2020; 93:95-114. [PMID: 32599145 DOI: 10.1016/j.matbio.2020.06.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/15/2020] [Accepted: 06/21/2020] [Indexed: 01/08/2023]
Abstract
The identification of barely more than 20,000 human genes was amongst the most surprising outcomes of the human genome project. Alternative splicing provides an essential means of expanding the proteome, enabling a single gene to encode multiple, distinct isoforms by selective inclusion or exclusion of exons from mature mRNA. However, mis-regulation of this process is associated with most human diseases. Here, we examine the impact of post-transcriptional processing on extracellular matrix function, focusing on the complex alternative splicing patterns of tenascin-C, a molecule that can exist in as many as 500 different isoforms. We demonstrate that the pro-inflammatory activity of this endogenous innate immune trigger is controlled by inclusion or exclusion of a novel immunomodulatory site located within domains AD2AD1, identifying this as a mechanism that prevents unnecessary inflammation in healthy tissues but enables rapid immune cell mobilization and activation upon tissue damage, and defining how this goes awry in autoimmune disease.
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Affiliation(s)
- Sean P Giblin
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Anja Schwenzer
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Kim S Midwood
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.
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11
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Reinhard J, Wagner N, Krämer MM, Jarocki M, Joachim SC, Dick HB, Faissner A, Kakkassery V. Expression Changes and Impact of the Extracellular Matrix on Etoposide Resistant Human Retinoblastoma Cell Lines. Int J Mol Sci 2020; 21:ijms21124322. [PMID: 32560557 PMCID: PMC7352646 DOI: 10.3390/ijms21124322] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 06/05/2020] [Accepted: 06/10/2020] [Indexed: 12/12/2022] Open
Abstract
Retinoblastoma (RB) represents the most common malignant childhood eye tumor worldwide. Several studies indicate that the extracellular matrix (ECM) plays a crucial role in tumor growth and metastasis. Moreover, recent studies indicate that the ECM composition might influence the development of resistance to chemotherapy drugs. The objective of this study was to evaluate possible expression differences in the ECM compartment of the parental human cell lines WERI-RB1 (retinoblastoma 1) and Y79 and their Etoposide resistant subclones via polymerase chain reaction (PCR). Western blot analyses were performed to analyze protein levels. To explore the influence of ECM molecules on RB cell proliferation, death, and cluster formation, WERI-RB1 and resistant WERI-ETOR cells were cultivated on Fibronectin, Laminin, Tenascin-C, and Collagen IV and analyzed via time-lapse video microscopy as well as immunocytochemistry. We revealed a significantly reduced mRNA expression of the proteoglycans Brevican, Neurocan, and Versican in resistant WERI-ETOR compared to sensitive WERI-RB1 cells. Also, for the glycoproteins α1-Laminin, Fibronectin, Tenascin-C, and Tenascin-R as well as Collagen IV, reduced expression levels were observed in WERI-ETOR. Furthermore, a downregulation was detected for the matrix metalloproteinases MMP2, MMP7, MMP9, the tissue-inhibitor of metalloproteinase TIMP2, the Integrin receptor subunits ITGA4, ITGA5 and ITGB1, and all receptor protein tyrosine phosphatase β/ζ isoforms. Downregulation of Brevican, Collagen IV, Tenascin-R, MMP2, TIMP2, and ITGA5 was also verified in Etoposide resistant Y79 cells compared to sensitive ones. Protein levels of Tenascin-C and MMP-2 were comparable in both WERI cell lines. Interestingly, Fibronectin displayed an apoptosis-inducing effect on WERI-RB1 cells, whereas an anti-apoptotic influence was observed for Tenascin-C. Conversely, proliferation of WERI-ETOR cells was enhanced on Tenascin-C, while an anti-proliferative effect was observed on Fibronectin. In WERI-ETOR, cluster formation was decreased on the substrates Collagen IV, Fibronectin, and Tenascin-C. Collectively, we noted a different ECM mRNA expression and behavior of Etoposide resistant compared to sensitive RB cells. These findings may indicate a key role of ECM components in chemotherapy resistance formation of RB.
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Affiliation(s)
- Jacqueline Reinhard
- Department of Cell Morphology and Molecular Neurobiology, Faculty of Biology and Biotechnology, Ruhr-University Bochum, Universitaetsstrasse 150, 44780 Bochum, Germany; (N.W.); (M.M.K.); (M.J.); (A.F.)
- Correspondence: (J.R.); (V.K.); Tel.: +49-234-32-24-314 (J.R.); +49-451-500-43911 (V.K.); Fax: +49-234-32-143-13 (J.R.); +49-451-500-43914 (V.K.)
| | - Natalie Wagner
- Department of Cell Morphology and Molecular Neurobiology, Faculty of Biology and Biotechnology, Ruhr-University Bochum, Universitaetsstrasse 150, 44780 Bochum, Germany; (N.W.); (M.M.K.); (M.J.); (A.F.)
| | - Miriam M. Krämer
- Department of Cell Morphology and Molecular Neurobiology, Faculty of Biology and Biotechnology, Ruhr-University Bochum, Universitaetsstrasse 150, 44780 Bochum, Germany; (N.W.); (M.M.K.); (M.J.); (A.F.)
| | - Marvin Jarocki
- Department of Cell Morphology and Molecular Neurobiology, Faculty of Biology and Biotechnology, Ruhr-University Bochum, Universitaetsstrasse 150, 44780 Bochum, Germany; (N.W.); (M.M.K.); (M.J.); (A.F.)
| | - Stephanie C. Joachim
- Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, In der Schornau 23-25, 44892 Bochum, Germany; (S.C.J.); (H.B.D.)
| | - H. Burkhard Dick
- Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, In der Schornau 23-25, 44892 Bochum, Germany; (S.C.J.); (H.B.D.)
| | - Andreas Faissner
- Department of Cell Morphology and Molecular Neurobiology, Faculty of Biology and Biotechnology, Ruhr-University Bochum, Universitaetsstrasse 150, 44780 Bochum, Germany; (N.W.); (M.M.K.); (M.J.); (A.F.)
| | - Vinodh Kakkassery
- Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, In der Schornau 23-25, 44892 Bochum, Germany; (S.C.J.); (H.B.D.)
- Department of Ophthalmology, University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany
- Correspondence: (J.R.); (V.K.); Tel.: +49-234-32-24-314 (J.R.); +49-451-500-43911 (V.K.); Fax: +49-234-32-143-13 (J.R.); +49-451-500-43914 (V.K.)
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Cell-surface translocation of annexin A2 contributes to bleomycin-induced pulmonary fibrosis by mediating inflammatory response in mice. Clin Sci (Lond) 2020; 133:789-804. [PMID: 30902828 DOI: 10.1042/cs20180687] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 03/19/2019] [Accepted: 03/22/2019] [Indexed: 02/07/2023]
Abstract
Bleomycin, a widely used anti-cancer drug, may give rise to pulmonary fibrosis, a serious side effect which is associated with significant morbidity and mortality. Despite the intensive efforts, the precise pathogenic mechanisms of pulmonary fibrosis still remain to be clarified. Our previous study showed that bleomycin bound directly to annexin A2 (ANXA2, or p36), leading to development of pulmonary fibrosis by impeding transcription factor EB (TFEB)-induced autophagic flux. Here, we demonstrated that ANXA2 also played a critical role in bleomycin-induced inflammation, which represents another major cause of bleomycin-induced pulmonary fibrosis. We found that bleomycin could induce the cell surface translocation of ANXA2 in lung epithelial cells through exosomal secretion, associated with enhanced interaction between ANXA2 and p11. Knockdown of ANXA2 or blocking membrane ANXA2 mitigated bleomycin-induced activation of nuclear factor (NF)-κB pathway and production of pro-inflammatory cytokine IL-6 in lung epithelial cells. ANXA2-deficient (ANXA2-/-) mice treated with bleomycin exhibit reduced pulmonary fibrosis along with decreased cytokine production compared with bleomycin-challenged wild-type mice. Further, the surface ANXA2 inhibitor TM601 could ameliorate fibrotic and inflammatory response in bleomycin-treated mice. Taken together, our results indicated that, in addition to disturbing autophagic flux, ANXA2 can contribute to bleomycin-induced pulmonary fibrosis by mediating inflammatory response.
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Silencing of Tenascin-C Inhibited Inflammation and Apoptosis Via PI3K/Akt/NF-κB Signaling Pathway in Subarachnoid Hemorrhage Cell Model. J Stroke Cerebrovasc Dis 2020; 29:104485. [DOI: 10.1016/j.jstrokecerebrovasdis.2019.104485] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 09/22/2019] [Accepted: 10/11/2019] [Indexed: 12/19/2022] Open
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Hagiwara K, Harimoto N, Shirabe K. ASO Author Reflections: Clinical Significance of Large Tenascin C Splice Variants and Annexin A2 for Pancreatic Cancer. Ann Surg Oncol 2019; 27:931-932. [PMID: 31758283 DOI: 10.1245/s10434-019-08009-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Indexed: 11/18/2022]
Affiliation(s)
- Kei Hagiwara
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Norifumi Harimoto
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan.
| | - Ken Shirabe
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
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Hagiwara K, Harimoto N, Yokobori T, Muranushi R, Hoshino K, Gantumur D, Yamanaka T, Ishii N, Tsukagoshi M, Igarashi T, Tanaka H, Watanabe A, Kubo N, Araki K, Hosouchi Y, Shirabe K. High Co-expression of Large Tenascin C Splice Variants in Stromal Tissue and Annexin A2 in Cancer Cell Membranes is Associated with Poor Prognosis in Pancreatic Cancer. Ann Surg Oncol 2019; 27:924-930. [PMID: 31463696 DOI: 10.1245/s10434-019-07708-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND Pancreatic cancer tissue contains abundant stromal components, including extracellular matrix proteins such as tenascin C (TNC), which exists as large (TNC-L) and non-large splice variants. Here, we examined human pancreatic cancer specimens for the expression of total TNC (TNC-ALL) and TNC-L in the stroma and annexin A2 (ANXA2), a cell surface receptor for TNC, and evaluated their significance as prognostic markers for pancreatic cancer. METHODS Expression of ANXA2, TNC-ALL, and TNC-L was examined in 106 pancreatic cancer tissues from patients who underwent curative resection and who had not received prior therapy or surgery. Protein expression was measured by immunohistochemistry and scored on a semi-quantitative scale. The relationships between protein expression, clinicopathological factors, and prognosis were evaluated by Cox proportional hazards analysis. RESULTS TNC-ALL and TNC-L were detected mainly in the stroma, whereas ANXA2 was predominantly expressed in cancer cell membranes. TNC-ALL was also expressed in non-tumor pancreatic tissue. High levels of stromal TNC-L and membranous ANXA2, but not stromal TNC-ALL, were independently associated with cancer progression and poor prognosis. Moreover, high co-expression of stromal TNC-L and membranous ANXA2 was a superior indicator of poor prognosis compared with detection of TNC-ALL, TNC-L, or ANXA2 alone. CONCLUSIONS Our data suggest that co-expression of stromal TNC-L and membranous ANXA2 is a poor prognostic marker compared with detection of TNC-L or ANXA2 alone for pancreatic cancer patients. Additionally, targeting of crosstalk between stromal TNC and cancer cell ANXA2 could be a promising therapeutic strategy to overcome refractory pancreatic cancer.
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Affiliation(s)
- Kei Hagiwara
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Norifumi Harimoto
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan.
| | - Takehiko Yokobori
- Department of Innovative Cancer Immunotherapy, Gunma University, Maebashi, Japan.,Gunma University Initiative for Advanced Research (GIAR), Maebashi, Japan
| | - Ryo Muranushi
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Kouki Hoshino
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Dorgormaa Gantumur
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Takahiro Yamanaka
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Norihiro Ishii
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Mariko Tsukagoshi
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan.,Department of Innovative Cancer Immunotherapy, Gunma University, Maebashi, Japan
| | - Takamichi Igarashi
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Hiroshi Tanaka
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Akira Watanabe
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Norio Kubo
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Kenichiro Araki
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Yasuo Hosouchi
- Department of Surgery and Laparoscopic Surgery, Gunma Prefecture Saiseikai Maebashi Hospital, Maebashi, Japan
| | - Ken Shirabe
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
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16
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Annexin A2-mediated cancer progression and therapeutic resistance in nasopharyngeal carcinoma. J Biomed Sci 2018; 25:30. [PMID: 29598816 PMCID: PMC5877395 DOI: 10.1186/s12929-018-0430-8] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 03/20/2018] [Indexed: 02/07/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a head and neck cancer with poor clinical outcomes and insufficient treatments in Southeast Asian populations. Although concurrent chemoradiotherapy has improved recovery rates of patients, poor overall survival and low efficacy are still critical problems. To improve the therapeutic efficacy, we focused on a tumor-associated protein called Annexin A2 (ANXA2). This review summarizes the mechanisms by which ANXA2 promotes cancer progression (e.g., proliferation, migration, the epithelial-mesenchymal transition, invasion, and cancer stem cell formation) and therapeutic resistance (e.g., radiotherapy, chemotherapy, and immunotherapy). These mechanisms gave us a deeper understanding of the molecular aspects of cancer progression, and further provided us with a great opportunity to overcome therapeutic resistance of NPC and other cancers with high ANXA2 expression by developing this prospective ANXA2-targeted therapy.
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Abstract
AIM to establish a relationship between the main markers tumor stem cells (TSCs), CD44, and CD24, the level of tenascin C production, and chemoresistance in triple-negative breast cancer (BC). SUBJECTS AND METHODS Thirty biopsy specimens from triple-negative BC patients who had conventionally received preoperative chemotherapy followed by surgery were selected in the investigation. All the selected patients were conventionally assigned to neoadjuvant polychemotherapy (PCT) with paclitaxel and carboplatin. The surgical specimens were analyzed in relation to the degree of a tumor morphological response to PCT. The magnitude of the health-promoting effect of neoadjuvant therapy was evaluated according to the residual cancer burden (RCB) system using an on-line calculator; RCB was categorized into classes (from RCB-0 to RCB-III). The markers CD44, СD24, and tenascin C were identified by the standard immunoperoxidase method in the primary biopsies. RESULTS Varying morphological responses of triple-negative breast cancer to PCT were revealed, which showed resistance in 60% of the cases. The chemoresistance found in most (87%) cases coincided with the identification of the CD44+/CD24low/- profile. The detection of the higher production of the extracellular matrix tenascin C participating in the formation of the TSC niche fully combined with the CD44+/CD24low/- phenotype; while the maximum response to tenascin C was noted in the cases differing in not only a lack of responses to PCTs, but also in the most aggressive course in conjunction with metastatic disease. CONCLUSION Immunohistochemical analysis shows that the unique association between the CD44+/CD24low/- phenotype and the pronounced production of tenascin C may have a prognostic potential, prospectively indicating the inefficiency of neoadjuvant PCT, in particular that with platinum derivatives, which is used for the standard treatment of triple-negative BC. Taking into account the role of tenascin C in invasion, metastasis, and chemoresistance, it per se may be considered as a promising target for the targeted and/or combined therapy of triple-negative BC.
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Affiliation(s)
- O P Popova
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
| | - S Yu Bogomazova
- Treatment and Rehabilitation Center, Ministry of Health of Russia, Moscow, Russia
| | - A A Ivanov
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
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Foley K, Muth S, Jaffee E, Zheng L. Hedgehog signaling stimulates Tenascin C to promote invasion of pancreatic ductal adenocarcinoma cells through Annexin A2. Cell Adh Migr 2017; 11:514-523. [PMID: 28152318 PMCID: PMC5810754 DOI: 10.1080/19336918.2016.1259057] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 11/01/2016] [Accepted: 11/04/2016] [Indexed: 01/17/2023] Open
Abstract
Pancreatic adenocarcinoma (PDA) is characterized by a dense desmoplastic reaction that comprises 60-90% of the tumor, while only 10-40% of the tumor is composed of malignant epithelial cells. This desmoplastic reaction is composed of stromal fibroblast cells, extracellular matrix proteins, and immune cells. Accumulating evidence has suggested that the stromal and epithelial cell compartments interact during the pathogenesis of this disease. Therefore, it is important to identify the signaling pathways responsible for this interaction to better understand the mechanisms by which PDA invades and metastasizes. Here, we show that secreted stromal factors induce invasion of PDA cells. Specifically, hedgehog signaling from the tumor cells induces tenascin C (TnC) secretion from the stromal cells that acts back upon the tumor cells in a paracrine fashion to induce the invasion of PDA cells through its' receptor annexin A2 (AnxA2). Therefore, blocking the interaction between TnC and AnxA2 has the potential to prevent liver metastasis in PDA.
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Affiliation(s)
- Kelly Foley
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Stephen Muth
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Elizabeth Jaffee
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lei Zheng
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Zhang M, Chen D, Zhen Z, Ao J, Yuan X, Gao X. Annexin A2 positively regulates milk synthesis and proliferation of bovine mammary epithelial cells through the mTOR signaling pathway. J Cell Physiol 2017; 233:2464-2475. [DOI: 10.1002/jcp.26123] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 08/01/2017] [Indexed: 12/22/2022]
Affiliation(s)
- Minghui Zhang
- The Key Laboratory of Dairy Science of Education Ministry; Northeast Agricultural University; Heilongjiang Province China
| | - Dongying Chen
- The Key Laboratory of Dairy Science of Education Ministry; Northeast Agricultural University; Heilongjiang Province China
| | - Zhen Zhen
- The Key Laboratory of Dairy Science of Education Ministry; Northeast Agricultural University; Heilongjiang Province China
| | - Jinxia Ao
- The Key Laboratory of Dairy Science of Education Ministry; Northeast Agricultural University; Heilongjiang Province China
| | - Xiaohan Yuan
- The Key Laboratory of Dairy Science of Education Ministry; Northeast Agricultural University; Heilongjiang Province China
| | - Xuejun Gao
- The Key Laboratory of Dairy Science of Education Ministry; Northeast Agricultural University; Heilongjiang Province China
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Wang Z, Wei Q, Han L, Cao K, Lan T, Xu Z, Wang Y, Gao Y, Xue J, Shan F, Feng J, Xie X. Tenascin-c renders a proangiogenic phenotype in macrophage via annexin II. J Cell Mol Med 2017; 22:429-438. [PMID: 28857429 PMCID: PMC5742692 DOI: 10.1111/jcmm.13332] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Accepted: 06/21/2017] [Indexed: 12/31/2022] Open
Abstract
Tenascin-c is an extracellular matrix glycoprotein, the expression of which relates to the progression of atherosclerosis, myocardial infarction and heart failure. Annexin II acts as a cell surface receptor of tenascin-c. This study aimed to delineate the role of tenascin-c and annexin II in macrophages presented in atherosclerotic plaque. Animal models with atherosclerotic lesions were established using ApoE-KO mice fed with high-cholesterol diet. The expression of tenascin-c and annexin II in atherosclerotic lesions was determined by qRT-PCR, Western blot and immunohistochemistry analysis. Raw 264.7 macrophages and human primary macrophages were exposed to 5, 10 and 15 μg/ml tenascin-c for 12 hrs. Cell migration as well as the proangiogenic ability of macrophages was examined. Additionally, annexin II expression was delineated in raw 264.7 macrophages under normal condition (20% O2 ) for 12 hrs or hypoxic condition (1% O2 ) for 6-12 hrs. The expression of tenascin-c and annexin II was markedly augmented in lesion aorta. Tenascin-c positively regulated macrophage migration, which was dependent on the expression of annexin II in macrophages. VEGF release from macrophages and endothelial tube induction by macrophage were boosted by tenascin-c and attenuated by annexin II blocking. Furthermore, tenascin-c activated Akt/NF-κB and ERK signalling through annexin II. Lastly, hypoxia conditioning remarkably facilitates annexin II expression in macrophages through hypoxia-inducible factor (HIF)-1α but not HIF-2α. In conclusion, tenascin-c promoted macrophage migration and VEGF expression through annexin II, the expression of which was modulated by HIF-1α.
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Affiliation(s)
- Zhiyang Wang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an, China
| | - Qi Wei
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an, China
| | - Liang Han
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an, China
| | - Keqing Cao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an, China
| | - Tianfeng Lan
- Institute of Integrated Medical Information, Xi'an, China
| | - Zhenjie Xu
- Institute of Integrated Medical Information, Xi'an, China
| | - Yingjuan Wang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an, China
| | - Yuan Gao
- Department of Traditional Chinese Medicine, College of Life Science, Northwest University, Xi'an, China
| | - Jing Xue
- Department of Traditional Chinese Medicine, College of Life Science, Northwest University, Xi'an, China
| | - Fei Shan
- Department of Cardiovascular Surgery, Affiliated Hospital of Yan'an University, Yan'an, China
| | - Jun Feng
- Department of Vascular Surgery, the First Affiliated Hospital of Xi'an JiaoTong University, Xi'an, China
| | - Xin Xie
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an, China.,Institute of Integrated Medical Information, Xi'an, China
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Rajabpour A, Rajaei F, Teimoori-Toolabi L. Molecular alterations contributing to pancreatic cancer chemoresistance. Pancreatology 2017; 17:310-320. [PMID: 28065383 DOI: 10.1016/j.pan.2016.12.013] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2016] [Revised: 12/27/2016] [Accepted: 12/28/2016] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most common causes of cancer-related death all over the world. This disease is difficult to treat and patients have an overall 5-year survival rate of less than 5%. Although two drugs, gemcitabine (GEM) and 5-fluorouracil (5-FU) have been shown to improve the survival rate of patients systematically, they do not increase general survival to a clinically acceptable degree. Lack of ideal clinical response of pancreatic cancer patients to chemotherapy is likely to be due to intrinsic and acquired chemoresistance of tumor cells. Various mechanisms of drug resistance have been investigated in pancreatic cancer, including genetic and epigenetic changes in particular genes or signaling pathways. In addition, evidence suggests that microRNAs (miRNAs) play significant roles as key regulators of gene expression in many cellular processes, including drug resistance. Understanding underlying genes and mechanisms of drug resistance in pancreatic cancer is critical to develop new effective treatments for this deadly disease. This review illustrates the genes and miRNAs involved in resistance to gemcitabine in pancreatic cancer.
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Affiliation(s)
- Azam Rajabpour
- Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran; Department of Molecular Medicine, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran; Department of Molecular Medicine, Pasteur Institute of Iran, Tehran, Iran
| | - Farzad Rajaei
- Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran; Department of Molecular Medicine, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
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Thakur R, Mishra DP. Matrix reloaded: CCN, tenascin and SIBLING group of matricellular proteins in orchestrating cancer hallmark capabilities. Pharmacol Ther 2016; 168:61-74. [DOI: 10.1016/j.pharmthera.2016.09.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Kling T, Ferrarese R, Ó hAilín D, Johansson P, Heiland DH, Dai F, Vasilikos I, Weyerbrock A, Jörnsten R, Carro MS, Nelander S. Integrative Modeling Reveals Annexin A2-mediated Epigenetic Control of Mesenchymal Glioblastoma. EBioMedicine 2016; 12:72-85. [PMID: 27667176 PMCID: PMC5078587 DOI: 10.1016/j.ebiom.2016.08.050] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 08/26/2016] [Accepted: 08/31/2016] [Indexed: 12/02/2022] Open
Abstract
Glioblastomas are characterized by transcriptionally distinct subtypes, but despite possible clinical relevance, their regulation remains poorly understood. The commonly used molecular classification systems for GBM all identify a subtype with high expression of mesenchymal marker transcripts, strongly associated with invasive growth. We used a comprehensive data-driven network modeling technique (augmented sparse inverse covariance selection, aSICS) to define separate genomic, epigenetic, and transcriptional regulators of glioblastoma subtypes. Our model identified Annexin A2 (ANXA2) as a novel methylation-controlled positive regulator of the mesenchymal subtype. Subsequent evaluation in two independent cohorts established ANXA2 expression as a prognostic factor that is dependent on ANXA2 promoter methylation. ANXA2 knockdown in primary glioblastoma stem cell-like cultures suppressed known mesenchymal master regulators, and abrogated cell proliferation and invasion. Our results place ANXA2 at the apex of a regulatory cascade that determines glioblastoma mesenchymal transformation and validate aSICS as a general methodology to uncover regulators of cancer subtypes.
Glioblastoma, a form of brain cancer, is characterised by distinct molecular subtypes: proneural, classical and mesenchymal. We used a comprehensive data-driven strategy, aSICS, to elucidate the cellular mechanisms behind the subtypes. Epigenetic control of Annexin A2 (ANXA2) was predicted and confirmed to determine the invasive mesenchymal subtype. Most cancers have distinct and clinically relevant transcriptional subtypes, but the underlying cellular mechanism behind such subtypes is often hard to resolve. We show that joint analysis across several layers of genomics data can uncover subtype regulators with good accuracy. Our method is applied to the brain cancer glioblastoma multiforme (GBM), revealing that the invasive mesenchymal subtype is driven by epigenetic modulation of the expression of Annexin A2 (ANXA2). Our analysis adds significantly to our understanding of brain cancer subtypes and open for new potential treatment options. The proposed computational technique can be applied to other cancers as well.
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Affiliation(s)
- Teresia Kling
- Sahlgrenska Cancer Center, Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Roberto Ferrarese
- Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
| | - Darren Ó hAilín
- Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany; Faculty of Biology, Schnzlestrasse 1, University of Freiburg, D-79104 Freiburg, Germany
| | - Patrik Johansson
- Dept of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbecklaboratoriet, SE-751 85 Uppsala, Sweden
| | - Dieter Henrik Heiland
- Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
| | - Fangping Dai
- Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
| | - Ioannis Vasilikos
- Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
| | - Astrid Weyerbrock
- Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
| | - Rebecka Jörnsten
- Mathematical Sciences, University of Gothenburg and Chalmers University of Technology, SE-412 96 Gothenburg, Sweden
| | - Maria Stella Carro
- Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
| | - Sven Nelander
- Dept of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbecklaboratoriet, SE-751 85 Uppsala, Sweden.
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Piccinini AM, Zuliani-Alvarez L, Lim JMP, Midwood KS. Distinct microenvironmental cues stimulate divergent TLR4-mediated signaling pathways in macrophages. Sci Signal 2016; 9:ra86. [PMID: 27577261 DOI: 10.1126/scisignal.aaf3596] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Macrophages exhibit a phenotypic plasticity that enables them to orchestrate specific immune responses to distinct threats. The microbial product lipopolysaccharide (LPS) and the extracellular matrix glycoprotein tenascin-C are released during bacterial infection and tissue injury, respectively, and both activate Toll-like receptor 4 (TLR4). We found that these two TLR4 ligands stimulated distinct signaling pathways in macrophages, resulting in cells with divergent phenotypes. Although macrophages activated by LPS or tenascin-C displayed some common features, including activation of nuclear factor κB and mitogen-activated protein kinase signaling and cytokine synthesis, each ligand stimulated the production of different subsets of cytokines and generated different phosphoproteomic signatures. Moreover, tenascin-C promoted the generation of macrophages that exhibited increased synthesis and phosphorylation of extracellular matrix components, whereas LPS stimulated the production of macrophages that exhibited an enhanced capacity to degrade the matrix. These data reveal how the activation of one pattern recognition receptor by different microenvironmental cues generates macrophage with distinct phenotypes.
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Affiliation(s)
- Anna M Piccinini
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Headington, Oxford OX3 7FY, U.K
| | - Lorena Zuliani-Alvarez
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Headington, Oxford OX3 7FY, U.K
| | - Jenny M P Lim
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Headington, Oxford OX3 7FY, U.K
| | - Kim S Midwood
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Headington, Oxford OX3 7FY, U.K.
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25
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Abstract
Tenascin-C is a large, multimodular, extracellular matrix glycoprotein that exhibits a very restricted pattern of expression but an enormously diverse range of functions. Here, we discuss the importance of deciphering the expression pattern of, and effects mediated by, different forms of this molecule in order to fully understand tenascin-C biology. We focus on both post transcriptional and post translational events such as splicing, glycosylation, assembly into a 3D matrix and proteolytic cleavage, highlighting how these modifications are key to defining tenascin-C function.
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Key Words
- AD1/AD2, additional domain 1/ additional domain 2
- ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs
- ASMCs, aortic smooth muscle cells
- BDNF, brain derived neurotrophic factor
- BHKs, baby hamster kidney cells
- BMP, bone morphogenetic protein
- CA19–9, carbohydrate antigen 19–9
- CALEB, chicken acidic leucine-rich EGF-like domain containing brain protein
- CEA, carcinoembryonic antigen
- CNS, central nervous system
- CRC, colorectal carcinomas
- CTGF, connective tissue growth factor
- DCIS, ductal carcinoma in-situ
- ECM, extracellular matrix
- EDA-FN, extra domain A containing fibronectin
- EDB-FN, extra domain B containing fibronectin
- EGF-L, epidermal growth factor-like
- EGF-R, epidermal growth factor receptor
- ELISPOT, enzyme-linked immunospot assay
- FBG, fibrinogen-like globe
- FGF2, fibroblast growth factor 2
- FGF4, fibroblast growth factor 4
- FN, fibronectin
- FNIII, fibronectin type III-like repeat
- GMEM, glioma-mesenchymal extracellular matrix antigen
- GPI, glycosylphosphatidylinositol
- HB-EGF, heparin-binding EGF-like growth factor
- HCEs, immortalized human corneal epithelial cell line
- HGF, hepatocyte growth factor
- HNK-1, human natural killer-1
- HSPGs, heparan sulfate proteoglycans
- HUVECs, human umbilical vein endothelial cells
- ICC, immunocytochemistry
- IF, immunofluorescence
- IFNγ, interferon gamma
- IGF, insulin-like growth factor
- IGF-BP, insulin-like growth factor-binding protein
- IHC, immunohistochemistry
- IL, interleukin
- ISH, in situ hybridization
- LPS, lipopolysaccharide
- MMP, matrix metalloproteinase
- MPNSTs, malignant peripheral nerve sheath tumors
- Mr, molecular mass
- NB, northern blot
- NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells
- NK, natural killer cells
- NSCLC, non-small cell lung carcinoma
- NSCs, neural stem cells
- NT, neurotrophin
- PAMPs, pathogen-associated molecular patterns
- PDGF, platelet derived growth factor
- PDGF-Rβ, platelet derived growth factor receptor β
- PIGF, phosphatidylinositol-glycan biosynthesis class F protein
- PLCγ, phospholipase-C gamma
- PNS, peripheral nervous system
- PTPRζ1, receptor-type tyrosine-protein phosphatase zeta
- RA, rheumatoid arthritis
- RCC, renal cell carcinoma
- RD, rhabdomyosarcoma
- RGD, arginylglycylaspartic acid
- RT-PCR, real-time polymerase chain reaction
- SB, Southern blot
- SCC, squamous cell carcinoma
- SMCs, smooth muscle cells
- SVZ, sub-ventricular zone
- TA, tenascin assembly domain
- TGFβ, transforming growth factor β
- TIMP, tissue inhibitor of metalloproteinases
- TLR4, toll-like receptor 4
- TNFα, tumor necrosis factor α
- TSS, transcription start site
- UBC, urothelial bladder cancer
- UCC, urothelial cell carcinoma
- VEGF, vascular endothelial growth factor
- VSMCs, vascular smooth muscle cells
- VZ, ventricular zone
- WB, immunoblot/ western blot
- bFGF, basic fibroblast growth factor
- biosynthesis
- c, charged
- cancer
- ccRCC, clear cell renal cell carcinoma
- chRCC, chromophobe-primary renal cell carcinoma
- development
- glycosylation
- mAb, monoclonal antibody
- matrix assembly
- mitogen-activated protein kinase, MAPK
- pHo, extracellular pH
- pRCC, papillary renal cell carcinoma
- proteolytic cleavage
- siRNA, small interfering RNA
- splicing
- tenascin-C
- therapeutics
- transcription
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Affiliation(s)
- Sean P Giblin
- a Nuffield Department of Orthopaedics; Rheumatology and Musculoskeletal Sciences ; Kennedy Institute of Rheumatology; University of Oxford ; Oxford , UK
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Abstract
The extracellular matrix protein tenascin C (TNC) is a large glycoprotein expressed in connective tissues and stem cell niches. TNC over-expression is repeatedly observed in cancer, often at the invasive tumor front, and is associated with poor clinical outcome in several malignancies. The link between TNC expression and poor survival in cancer patients suggests a role for TNC in metastatic progression, which is responsible for the majority of cancer related deaths. Indeed, functional studies using mouse models are revealing new roles of TNC in cancer progression and underscore its important contribution to the development of metastasis. TNC has a pleiotropic role in advancing metastasis by promoting migratory and invasive cell behavior, angiogenesis and cancer cell viability under stress. TNC is an essential component of the metastatic niche and modulates stem cell signaling within the niche. This may be crucial for the fitness of disseminated cancer cells confronted with a foreign environment in secondary organs, that can exert a strong selective pressure on invading cells. TNC is a compelling example of how an extracellular matrix protein can provide a molecular context that is imperative to cancer cell fitness in metastasis.
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Affiliation(s)
- Camille M Lowy
- a Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH) ; Heidelberg , Germany
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Hu H, Zhao J, Zhang M. Expression of Annexin A2 and Its Correlation With Drug Resistance and Recurrence of Bladder Cancer. Technol Cancer Res Treat 2015; 15:NP61-NP68. [PMID: 26637476 DOI: 10.1177/1533034615617078] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Revised: 09/10/2015] [Accepted: 10/01/2015] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVE To explore the expressions of annexin A2 in bladder cancer cell lines and bladder cancer tissues, we want to find the relationship among annexin A2, drug resistance, and recurrence of bladder cancer. METHODS Our laboratory established the PUMC-91 bladder cancer cell line against gradient concentration of Adriamycin (0.3, 0.6, and 1.0 μg/mL), and we also collected 60 cases of surgically resected bladder cancer recurrent tissue samples. The tissues were classified into 2 groups according to the frequency of recurrence (<6 months and >2 years) after initial surgery. The method of immunohistochemistry was used to examine the differences in the expression of annexin A2. RESULTS There were statistical differences in annexin A2 among normal bladder epithelial cell line SV-HUC-1, PUMC-91, PUMC-91 against 0.3 μg/mL Adriamycin, and PUMC-91 against 1.0 μg/mL Adriamycin (P < .05). The expressions of Annexin A2 were found to be higher than those that recurred at >2 years (P = .002) in the bladder cancer tissues and that recurred at <6 months after initial surgery. It was also associated with invasion depth (stage) of bladder cancer, such as higher expression in T2 (invasive muscular) group than Tis (carcinoma in situ) and T1 (invasive mucosa lamina propria) groups (P = .003 and P = .000, respectively). But, it did not correlate with the differentiation (grade) of cancer cells in bladder cancer tissues (P = .593). CONCLUSION Annexin A2 can act as a valuable biomarker for predicting the drug resistance and recurrence of bladder cancer.
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Affiliation(s)
- Huihui Hu
- Department of Clinical Laboratory, Beijing Shijitan Hospital, Capital Medical University, Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
| | - Jin Zhao
- Department of Clinical Laboratory, Beijing Shijitan Hospital, Capital Medical University, Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
| | - Man Zhang
- Department of Clinical Laboratory, Beijing Shijitan Hospital, Capital Medical University, Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
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Intracellular annexin A2 regulates NF-κB signaling by binding to the p50 subunit: implications for gemcitabine resistance in pancreatic cancer. Cell Death Dis 2015; 6:e1606. [PMID: 25611381 PMCID: PMC4669756 DOI: 10.1038/cddis.2014.558] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 11/26/2014] [Accepted: 11/26/2014] [Indexed: 12/18/2022]
Abstract
Annexin A2 (ANXA2) expression is highly upregulated in many types of cancer. Although cell surface localization of ANXA2 has been reported to have a critical role in the progression and metastasis of a variety of tumors, including pancreatic cancer, the biological role of intracellular ANXA2 is not fully understood. Herein the role of intracellular ANXA2 was investigated in a pancreatic cancer cell line. We first determined whether ANXA2 is involved in NF-κB signaling pathways. ANXA2 bound to the p50 subunit of NF-κB in a calcium-independent manner, and the ANXA2–p50 complex translocated into the nucleus. Furthermore, ANXA2 increased the transcriptional activity of NF-κB in both the resting and activated states and upregulated the transcription of several target genes downstream of NF-κB, including that encoding interleukin (IL)-6, which contributes to anti-apoptotic signaling. In Mia-Paca2 cells, we determined the effects of wild-type ANXA2 and an ANXA2 mutant, Y23A, which suppresses the cell surface localization, on upregulation of NF-κB transcriptional activity and secretion of IL-6. Both wild-type and Y23A ANXA2 induced anti-apoptotic effects in response to treatment with tumor necrosis factor-α or gemcitabine. Based on these results, we suggest that ANXA2 mediates resistance to gemcitabine by directly increasing the activity of NF-κB. Collectively, these data may provide additional information about the biological role of ANXA2 in pancreatic cancer and suggest that ANXA2 is a potential biomarker for the drug resistance phenotype and a candidate therapeutic target for the treatment of pancreatic cancer.
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29
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Fang WB, Yao M, Cheng N. Priming cancer cells for drug resistance: role of the fibroblast niche. ACTA ACUST UNITED AC 2014; 9:114-126. [PMID: 25045348 DOI: 10.1007/s11515-014-1300-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Conventional and targeted chemotherapies remain integral strategies to treat solid tumors. Despite the large number of anti-cancer drugs available, chemotherapy does not completely eradicate disease. Disease recurrence and the growth of drug resistant tumors remain significant problems in anti-cancer treatment. To develop more effective treatment strategies, it is important to understand the underlying cellular and molecular mechanisms of drug resistance. It is generally accepted that cancer cells do not function alone, but evolve through interactions with the surrounding tumor microenvironment. As key cellular components of the tumor microenvironment, fibroblasts regulate the growth and progression of many solid tumors. Emerging studies demonstrate that fibroblasts secrete a multitude of factors that enable cancer cells to become drug resistant. This review will explore how fibroblast secretion of soluble factors act on cancer cells to enhance cancer cell survival and cancer stem cell renewal, contributing to the development of drug resistant cancer.
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Affiliation(s)
- Wei Bin Fang
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Min Yao
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Nikki Cheng
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
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30
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Waters KM, Stenoien DL, Sowa MB, von Neubeck C, Chrisler WB, Tan R, Sontag RL, Weber TJ. Annexin A2 modulates radiation-sensitive transcriptional programming and cell fate. Radiat Res 2012; 179:53-61. [PMID: 23148505 DOI: 10.1667/rr3056.1] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
We previously established annexin A2 as a radioresponsive protein associated with anchorage independent growth in murine epidermal cells. In this study, we demonstrate annexin A2 nuclear translocation in human skin organotypic culture and murine epidermal cells after exposure to X radiation (10-200 cGy), supporting a conserved nuclear function for annexin A2. Whole genome expression profiling in the presence and absence of annexin A2 [shRNA] identified fundamentally altered transcriptional programming that changes the radioresponsive transcriptome. Bioinformatics predicted that silencing AnxA2 may enhance cell death responses to stress in association with reduced activation of pro-survival signals such as nuclear factor kappa B. This prediction was validated by demonstrating a significant increase in sensitivity toward tumor necrosis factor alpha-induced cell death in annexin A2 silenced cells, relative to vector controls, associated with reduced nuclear translocation of RelA (p65) following tumor necrosis factor alpha treatment. These observations implicate an annexin A2 niche in cell fate regulation such that AnxA2 protects cells from radiation-induced apoptosis to maintain cellular homeostasis at low-dose radiation.
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Affiliation(s)
- Katrina M Waters
- Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, Richland, Washington 99352, USA
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31
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Sato T, Kita K, Sugaya S, Suzuki T, Suzuki N. Extracellular release of annexin II from pancreatic cancer cells and resistance to anticancer drug-induced apoptosis by supplementation of recombinant annexin II. Pancreas 2012; 41:1247-54. [PMID: 22750966 DOI: 10.1097/mpa.0b013e31824f356f] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Extracellular microenvironment plays crucial roles in the development of cancers and chemoresistance. Pancreatic carcinoma is resistant to almost all chemotherapeutic agents. In this study, we identified annexin II in the medium from pancreatic cancer cells as a protein released into the extracellular environment. METHODS Medium from 5-hour cultures of various cancer cells was collected. Proteins in the medium were detected by molecular mass analysis and immunoblotting. Anticancer drug sensitivity of cells preincubated with or without recombinant annexin II (rANX II) was measured using crystal violet assay and colony survival assay. Apoptosis-related molecules were analyzed by immunoblotting. RESULTS Recombinant ANX II supplementation in the medium confers resistance to anticancer drugs, including cisplatin, 5-fluorouracil, and gemcitabine, in MiaPaCa-2 and AsPC-1 cells. In MiaPaCa-2 cells, rANX II supplementation resulted in suppression of caspase-3 activation associated with increased Bcl-2/Bax ratios. Suppression of cisplatin-induced cell death by rANX II supplementation was canceled by inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase signal pathways. CONCLUSIONS The current study is the first report to demonstrate that supplementation of rANX II in the medium increased resistance to anticancer drugs in pancreatic cancer cells. Recombinant ANX II exerts cell death-suppressive function by antagonizing cisplatin-induced apoptosis.
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Affiliation(s)
- Tetsuo Sato
- Department of Environmental Biochemistry, Graduate School of Medicine, Chiba University, Chiba, Japan
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32
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Kagawa S, Takano S, Yoshitomi H, Kimura F, Satoh M, Shimizu H, Yoshidome H, Ohtsuka M, Kato A, Furukawa K, Matsushita K, Nomura F, Miyazaki M. Akt/mTOR signaling pathway is crucial for gemcitabine resistance induced by Annexin II in pancreatic cancer cells. J Surg Res 2012; 178:758-67. [PMID: 22726648 DOI: 10.1016/j.jss.2012.05.065] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Revised: 05/14/2012] [Accepted: 05/22/2012] [Indexed: 01/10/2023]
Abstract
BACKGROUND Although gemcitabine has been widely used as a first-line chemo reagent for patients with pancreatic cancer, the response rate remains low. We previously identified Annexin II as a factor involved in gemcitabine resistance against pancreatic cancer. The aims of this study were to elucidate the signaling mechanism by which Annexin II induces gemcitabine resistance and to develop a new therapy that overcomes the resistance against gemcitabine. METHODS We compared the specific profiles of 12 targeted phosphorylated (p-) signaling proteins in gemcitabine-resistant (GEM-) and its wild-type pancreatic cancer cell lines (MIA PaCa-2) using the Bio-Plex assay system. We also evaluated the expression levels of Annexin II and two phosphoproteins, which showed different expressions in these two cell lines, by immunohistochemistry. RESULTS Annexin II overexpression was significantly associated with rapid recurrence after gemcitabine-adjuvant chemotherapy in patients with resected pancreatic cancer (P < 0.05). Bio-Plex analysis showed up-regulation of p-Akt in GEM-MIA PaCa-2 cells in which Annexin II is highly expressed. The expression level of p-Akt was significantly correlated with that of the downstream protein, p-mTOR, in pancreatic cancer tissues. Inhibition of mTOR phosphorylation canceled gemcitabine resistance in GEM-MIA PaCa-2 cells. CONCLUSIONS The Akt/mTOR pathway is involved in mechanisms of gemcitabine resistance induced by Annexin II in pancreatic cancer cells. This indicates that combination therapy with the mTOR inhibitor may overcome gemcitabine resistance. Annexin II as an indicator for selection of gemcitabine resistance could thus be applied to the development of novel tailor-made approaches for pancreatic cancer treatment.
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Affiliation(s)
- Shingo Kagawa
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
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Abstract
Tenascins are large glycoproteins found in embryonic and adult extracellular matrices. Of the four family members, two have been shown to be overexpressed in the microenvironment of solid tumours: tenascin-C and tenascin-W. The regular presence of these proteins in tumours suggests a role in tumourigenesis, which has been investigated intensively for tenascin-C and recently for tenascin-W as well. In this review, we follow a malignant cell starting from its birth through its potential metastatic journey and describe how tenascin-C and tenascin-W contribute to these successive steps of tumourigenesis. We consider the importance of the mechanical aspect in tenascin signalling. Furthermore, we discuss studies describing tenascin-C as an important component of stem cell niches and present examples reporting its role in cancer therapy resistance.
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Affiliation(s)
- Florence Brellier
- Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, Basel, Switzerland
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Momi N, Kaur S, Ponnusamy MP, Kumar S, Wittel UA, Batra SK. Interplay between smoking-induced genotoxicity and altered signaling in pancreatic carcinogenesis. Carcinogenesis 2012; 33:1617-28. [PMID: 22623649 DOI: 10.1093/carcin/bgs186] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Despite continuous research efforts directed at early diagnosis and treatment of pancreatic cancer (PC), the status of patients affected by this deadly malignancy remains dismal. Its notoriety with regard to lack of early diagnosis and resistance to the current chemotherapeutics is due to accumulating signaling abnormalities. Hoarding experimental and epidemiological evidences have established a direct correlation between cigarette smoking and PC risk. The cancer initiating/promoting nature of cigarette smoke can be attributed to its various constituents including nicotine, which is the major psychoactive component, and several other toxic constituents, such as nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and polycyclic aromatic hydrocarbons. These predominant smoke-constituents initiate a series of oncogenic events facilitating epigenetic alterations, self-sufficiency in growth signals, evasion of apoptosis, sustained angiogenesis, and metastasis. A better understanding of the molecular mechanisms underpinning these events is crucial for the prevention and therapeutic intervention against PC. This review presents various interconnected signal transduction cascades, the smoking-mediated genotoxicity, and genetic polymorphisms influencing the susceptibility for smoking-mediated PC development by modulating pivotal biological aspects such as cell defense/tumor suppression, inflammation, DNA repair, as well as tobacco-carcinogen metabolization. Additionally, it provides a large perspective toward tumor biology and the therapeutic approaches against PC by targeting one or several steps of smoking-mediated signaling cascades.
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Affiliation(s)
- Navneet Momi
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
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Efferth T, Greten HJ. In Silico Analysis of Microarray-Based Gene Expression Profiles Predicts Tumor Cell Response to Withanolides. MICROARRAYS 2012; 1:44-63. [PMID: 27605335 PMCID: PMC5007710 DOI: 10.3390/microarrays1010044] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2012] [Revised: 05/09/2012] [Accepted: 05/15/2012] [Indexed: 12/03/2022]
Abstract
Withania somnifera (L.) Dunal (Indian ginseng, winter cherry, Solanaceae) is widely used in traditional medicine. Roots are either chewed or used to prepare beverages (aqueous decocts). The major secondary metabolites of Withania somnifera are the withanolides, which are C-28-steroidal lactone triterpenoids. Withania somnifera extracts exert chemopreventive and anticancer activities in vitro and in vivo. The aims of the present in silico study were, firstly, to investigate whether tumor cells develop cross-resistance between standard anticancer drugs and withanolides and, secondly, to elucidate the molecular determinants of sensitivity and resistance of tumor cells towards withanolides. Using IC50 concentrations of eight different withanolides (withaferin A, withaferin A diacetate, 3-azerininylwithaferin A, withafastuosin D diacetate, 4-B-hydroxy-withanolide E, isowithanololide E, withafastuosin E, and withaperuvin) and 19 established anticancer drugs, we analyzed the cross-resistance profile of 60 tumor cell lines. The cell lines revealed cross-resistance between the eight withanolides. Consistent cross-resistance between withanolides and nitrosoureas (carmustin, lomustin, and semimustin) was also observed. Then, we performed transcriptomic microarray-based COMPARE and hierarchical cluster analyses of mRNA expression to identify mRNA expression profiles predicting sensitivity or resistance towards withanolides. Genes from diverse functional groups were significantly associated with response of tumor cells to withaferin A diacetate, e.g. genes functioning in DNA damage and repair, stress response, cell growth regulation, extracellular matrix components, cell adhesion and cell migration, constituents of the ribosome, cytoskeletal organization and regulation, signal transduction, transcription factors, and others.
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Affiliation(s)
- Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, Mainz 55128, Germany.
| | - Henry Johannes Greten
- Heidelberg School of Chinese Medicine, Karlsruher Straße 12, Heidelberg 69126, Germany.
- Biomedical Sciences Institute Abel Salazar, University of Porto, Porto 4050-313, Portugal.
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36
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Voutsadakis IA. Molecular predictors of gemcitabine response in pancreatic cancer. World J Gastrointest Oncol 2011; 3:153-64. [PMID: 22110842 PMCID: PMC3220724 DOI: 10.4251/wjgo.v3.i11.153] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2011] [Revised: 09/30/2011] [Accepted: 10/07/2011] [Indexed: 02/05/2023] Open
Abstract
Gemcitabine is one of the most used anti-neoplastic drugs with documented activity in almost all major localizations of cancer. In pancreatic cancer treatment, gemcitabine occupies a prominent place as a first line chemotherapy, partly because of the paucity of other efficacious chemotherapy options. In fact, only a minority of pancreatic cancer patients display a response or even stability of disease with the drug. There are currently no clinically applicable means of predicting which patient will derive a clinical benefit from gemcitabine although several proposed markers have been studied. These markers are proteins involved in drug up-take, activation and catabolism or proteins that define the ability of the cell to undergo apoptosis in response to the drug. Several of these markers are reviewed in this paper. We also briefly discuss the possible role of stem cells in drug resistance to gemcitabine.
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Affiliation(s)
- Ioannis A Voutsadakis
- Ioannis A Voutsadakis, Centre Pluridisciplinaire d'Oncologie, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland
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37
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Reynolds F, Panneer N, Tutino CM, Wu M, Skrabal WR, Moskaluk C, Kelly KA. A functional proteomic method for biomarker discovery. PLoS One 2011; 6:e22471. [PMID: 21811618 PMCID: PMC3139652 DOI: 10.1371/journal.pone.0022471] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2011] [Accepted: 06/22/2011] [Indexed: 01/29/2023] Open
Abstract
The sequencing of the human genome holds out the hope for personalized medicine, but it is clear that analysis of DNA or RNA content alone is not sufficient to understand most disease processes. Proteomic strategies that allow unbiased identification of proteins and their post-transcriptional and -translation modifications are an essential complement to genomic strategies. However, the enormity of the proteome and limitations in proteomic methods make it difficult to determine the targets that are particularly relevant to human disease. Methods are therefore needed that allow rational identification of targets based on function and relevance to disease. Screening methodologies such as phage display, SELEX, and small-molecule combinatorial chemistry have been widely used to discover specific ligands for cells or tissues of interest, such as tumors. Those ligands can be used in turn as affinity probes to identify their cognate molecular targets when they are not known in advance. Here we report an easy, robust and generally applicable approach in which phage particles bearing cell- or tissue-specific peptides serve directly as the affinity probes for their molecular targets. For proof of principle, the method successfully identified molecular binding partners, three of them novel, for 15 peptides specific for pancreatic cancer.
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Affiliation(s)
- Fred Reynolds
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America
- Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, United States of America
| | - Nivedha Panneer
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America
| | - Christopher M. Tutino
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America
| | - Michael Wu
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America
| | - William R. Skrabal
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America
| | - Christopher Moskaluk
- Department of Pathology, University of Virginia, Charlottesville, Virginia, United States of America
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, United States of America
| | - Kimberly A. Kelly
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America
- Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, United States of America
- * E-mail:
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