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1
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Detchou D, Barrie U. Interleukin 6 and cancer resistance in glioblastoma multiforme. Neurosurg Rev 2024; 47:541. [PMID: 39231832 DOI: 10.1007/s10143-024-02783-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 08/16/2024] [Accepted: 08/31/2024] [Indexed: 09/06/2024]
Abstract
Despite unprecedented survival in patients with glioblastoma (GB), the aggressive primary brain cancer remains largely incurable and its mechanisms of treatment resistance have gained particular attention. The cytokine interleukin 6 (IL-6) and its receptor weave through the hallmarks of malignant gliomas and may represent a key vulnerability to GB. Known for activating the STAT3 pathway in autocrine fashion, IL-6 is amplified in GB and has been recognized as a negative biomarker for GB prognosis, rendering it a putative target of novel GB therapies. While it has been recognized as a biologically active component of GB for three decades only with concurrent advances in understanding of complementary immunotherapy has the concept of targeting IL-6 for a human clinical trial gained scientific footing.
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Affiliation(s)
- Donald Detchou
- School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA.
| | - Umaru Barrie
- Department of Neurosurgery, New York University Grossman School of Medicine, New York City, NYC, USA
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2
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Maioru OV, Radoi VE, Coman MC, Hotinceanu IA, Dan A, Eftenoiu AE, Burtavel LM, Bohiltea LC, Severin EM. Developments in Genetics: Better Management of Ovarian Cancer Patients. Int J Mol Sci 2023; 24:15987. [PMID: 37958970 PMCID: PMC10647767 DOI: 10.3390/ijms242115987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 10/22/2023] [Accepted: 11/03/2023] [Indexed: 11/15/2023] Open
Abstract
The purpose of this article is to highlight the new advancements in molecular and diagnostic genetic testing and to properly classify all ovarian cancers. In this article, we address statistics, histopathological classification, molecular pathways implicated in ovarian cancer, genetic screening panels, details about the genes, and also candidate genes. We hope to bring new information to the medical field so as to better prevent and diagnose ovarian cancer.
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Affiliation(s)
- Ovidiu-Virgil Maioru
- Department of Medical Genetics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (O.-V.M.); (M.-C.C.); (A.D.); (A.-E.E.); (L.-M.B.); (L.-C.B.); (E.-M.S.)
| | - Viorica-Elena Radoi
- Department of Medical Genetics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (O.-V.M.); (M.-C.C.); (A.D.); (A.-E.E.); (L.-M.B.); (L.-C.B.); (E.-M.S.)
- “Alessandrescu-Rusescu” National Institute for Maternal and Child Health, 20382 Bucharest, Romania
| | - Madalin-Codrut Coman
- Department of Medical Genetics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (O.-V.M.); (M.-C.C.); (A.D.); (A.-E.E.); (L.-M.B.); (L.-C.B.); (E.-M.S.)
| | - Iulian-Andrei Hotinceanu
- Department of Medical Genetics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (O.-V.M.); (M.-C.C.); (A.D.); (A.-E.E.); (L.-M.B.); (L.-C.B.); (E.-M.S.)
| | - Andra Dan
- Department of Medical Genetics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (O.-V.M.); (M.-C.C.); (A.D.); (A.-E.E.); (L.-M.B.); (L.-C.B.); (E.-M.S.)
| | - Anca-Elena Eftenoiu
- Department of Medical Genetics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (O.-V.M.); (M.-C.C.); (A.D.); (A.-E.E.); (L.-M.B.); (L.-C.B.); (E.-M.S.)
| | - Livia-Mălina Burtavel
- Department of Medical Genetics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (O.-V.M.); (M.-C.C.); (A.D.); (A.-E.E.); (L.-M.B.); (L.-C.B.); (E.-M.S.)
| | - Laurentiu-Camil Bohiltea
- Department of Medical Genetics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (O.-V.M.); (M.-C.C.); (A.D.); (A.-E.E.); (L.-M.B.); (L.-C.B.); (E.-M.S.)
- “Alessandrescu-Rusescu” National Institute for Maternal and Child Health, 20382 Bucharest, Romania
| | - Emilia-Maria Severin
- Department of Medical Genetics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (O.-V.M.); (M.-C.C.); (A.D.); (A.-E.E.); (L.-M.B.); (L.-C.B.); (E.-M.S.)
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3
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Man Q, Li R, Bu L, Zhao Y, Liu B. Salivary non-apoptotic tumoral microvesicles: A potential progressive marker in oral cancer patients. J Cell Mol Med 2022; 26:5955-5965. [PMID: 36448260 PMCID: PMC9753445 DOI: 10.1111/jcmm.17461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 04/04/2022] [Accepted: 06/04/2022] [Indexed: 12/03/2022] Open
Abstract
Tumour cell-secreted microvesicles (MVs) contribute immensely to tumour progression. However, the role of tumoral salivary MVs in oral squamous cell carcinoma (OSCC) remains unclear. Herein, we elucidated the role of non-apoptotic salivary tumoral MVs in OSCC development, especially relating to the migration ability. We purified and compared non-apoptotic salivary tumoral MVs from 63 OSCC patients and orthotopic OSCC mice model. Next, we compared the protein difference between apoptotic and non-apoptotic MVs by Western blot, proteomics and flow cytometry from saliva and CAL27 cells. Finally, we collected the non-apoptotic MVs and co-cultured with normal oral epithelial cells, the migration ability was examined by wound healing assay and Western blot assay. Our results indicated that the levels of non-apoptotic tumoral S-MVs were significantly higher in OSCC patients with T3 to T4 stages than in patients with T1 to T2 stages or healthy donors. In OSCC mice model, we found elevations of non-apoptotic tumoral MVs associated with tumoral volume. EGFR overexpression increased the generation of non-apoptotic tumoral MVs which could significantly promote normal epithelial cell migration. In conclusion, elevated levels of non-apoptotic tumoral S-MVs are associated with clinicopathologic features of OSCC patients, implying that non-apoptotic tumoral S-MVs are a potential progressive marker of OSCC.
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Affiliation(s)
- Qi‐Wen Man
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of StomatologyWuhan UniversityWuhanChina,Department of Oral and Maxillofacial Head Neck Surgery, School & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Rui‐Fang Li
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Lin‐Lin Bu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of StomatologyWuhan UniversityWuhanChina,Department of Oral and Maxillofacial Head Neck Surgery, School & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Yi Zhao
- Department of Prosthodontics, School and Hospital of StomatologyWuhan UniversityWuhanChina
| | - Bing Liu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of StomatologyWuhan UniversityWuhanChina,Department of Oral and Maxillofacial Head Neck Surgery, School & Hospital of StomatologyWuhan UniversityWuhanChina
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4
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Naselsky W, Adhikary G, Shrestha S, Chen X, Ezeka G, Xu W, Friedberg JS, Eckert RL. Transglutaminase 2 enhances hepatocyte growth factor signaling to drive the mesothelioma cancer cell phenotype. Mol Carcinog 2022; 61:537-548. [PMID: 35319795 PMCID: PMC10074999 DOI: 10.1002/mc.23399] [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: 12/08/2021] [Accepted: 12/09/2021] [Indexed: 11/08/2022]
Abstract
Transglutaminase 2 (TG2) is an important mesothelioma cancer cell survival protein. However, the mechanism whereby TG2 maintains mesothelioma cell survival is not well understood. We present studies showing that TG2 drives hepatocyte growth factor (HGF)-dependent MET receptor signaling to maintain the aggressive mesothelioma cancer phenotype. TG2 increases HGF and MET messenger RNA and protein levels to enhance MET signaling. TG2 inactivation reduces MET tyrosine kinase activity to reduce cancer cell spheroid formation, invasion and migration. We also confirm that HGF/MET signaling is a biologically important mediator of TG2 action. Reducing MET level using genetic methods or treatment with MET inhibitors reduces spheroid formation, invasion and migration and this is associated with reduced MEK1/2 and ERK1/2. In addition, MEK1/2 and ERK1/2 inhibitors suppress the cancer phenotype. Moreover, MET knockout mesothelioma cells form 10-fold smaller tumors compared to wild-type cells and these tumors display reduced MET, MEK1/2, and ERK1/2 activity. These findings suggest that TG2 maintains HGF and MET levels in cultured mesothelioma cells and tumors to drive HGF/MET, MEK1/2, and ERK1/2 signaling to maintain the aggressive mesothelioma cancer phenotype.
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Affiliation(s)
- Warren Naselsky
- Department of Surgery, Division of Thoracic Oncology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Gautam Adhikary
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Suruchi Shrestha
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Xi Chen
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Geraldine Ezeka
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Wen Xu
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Joseph S Friedberg
- Department of Surgery, Division of Thoracic Oncology, University of Maryland School of Medicine, Baltimore, Maryland
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
| | - Richard L. Eckert
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland
- Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland
- Department of Reproductive Biology, University of Maryland School of Medicine, Baltimore, Maryland
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
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5
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Sayeed MA, Bracci M, Lucarini G, Lazzarini R, Di Primio R, Santarelli L. Regulation of microRNA using promising dietary phytochemicals: Possible preventive and treatment option of malignant mesothelioma. Biomed Pharmacother 2017; 94:1197-1224. [PMID: 28841784 DOI: 10.1016/j.biopha.2017.07.075] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 07/10/2017] [Accepted: 07/18/2017] [Indexed: 12/21/2022] Open
Abstract
Malignant mesothelioma (MM) is a very aggressive, lethal cancer, and its incidence is increasing worldwide. Development of multi-drug resistance, therapy related side-effects, and disease recurrence after therapy are the major problems for the successful treatment of MM. Emerging evidence indicates that dietary phytochemicals can exert anti-cancer activities by regulating microRNA expression. Until now, only one dietary phytochemical (ursolic acid) has been reported to have MM microRNA regulatory ability. A large number of dietary phytochemicals still remain to be tested. In this paper, we have introduced some dietary phytochemicals (curcumin, epigallocatechin gallate, quercetin, genistein, pterostilbene, resveratrol, capsaicin, ellagic acid, benzyl isothiocyanate, phenethyl isothiocyanate, sulforaphane, indole-3-carbinol, 3,3'-diindolylmethane, diallyl disulphide, betulinic acid, and oleanolic acid) which have shown microRNA regulatory activities in various cancers and could regulate MM microRNAs. In addition to microRNA regulatory activities, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, phenethyl isothiocyanate, and sulforaphane have anti-mesothelioma potentials, and pterostilbene, capsaicin, ellagic acid, benzyl isothiocyanate, indole-3-carbinol, 3,3'-diindolylmethane, diallyl disulphide, betulinic acid, and oleanolic acid have potentials to inhibit cancer by regulating the expression of various genes which are also known to be aberrant in MM.
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Affiliation(s)
- Md Abu Sayeed
- Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona 60126, Italy.
| | - Massimo Bracci
- Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona 60126, Italy
| | - Guendalina Lucarini
- Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona 60126, Italy
| | - Raffaella Lazzarini
- Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona 60126, Italy
| | - Roberto Di Primio
- Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona 60126, Italy
| | - Lory Santarelli
- Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona 60126, Italy
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6
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Abstract
Malignant mesothelioma is an asbestos-related cancer that occurs most commonly in the pleural space and is incurable. Increasing evidence suggests that aberrant receptor tyrosine kinase (RTK)-directed signalling plays a key role in the pathogenesis of this cancer. In the majority of mesotheliomas, up-regulated expression or signalling by Met, the receptor for hepatocyte growth factor (HGF) can be demonstrated. Following binding of ligand, Met relays signals that promote cell survival, proliferation, movement, invasiveness, branching morphogenesis and angiogenesis. Here we describe the HGF/Met axis and review the mechanisms that lead to the aberrant activation of this signalling system in mesothelioma. We also describe the cross-talk that occurs between HGF/Met and a number of other receptors, ligands and co-receptor systems. The prevalent occurrence of HGF/Met dysregulation in patients with mesothelioma sets the scene for the investigation of pharmaceutical inhibitors of this axis. In light of the inter-relationship between HGF/Met and other ligand receptor, combinatorial targeting strategies may provide opportunities for therapeutic advancement in this challenging tumour.
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7
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Chang JH, Huang YH, Cunningham CM, Han KY, Chang M, Seiki M, Zhou Z, Azar DT. Matrix metalloproteinase 14 modulates signal transduction and angiogenesis in the cornea. Surv Ophthalmol 2015; 61:478-97. [PMID: 26647161 DOI: 10.1016/j.survophthal.2015.11.006] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2015] [Revised: 11/12/2015] [Accepted: 11/23/2015] [Indexed: 11/16/2022]
Abstract
The cornea is transparent and avascular, and retention of these characteristics is critical to maintaining vision clarity. Under normal conditions, wound healing in response to corneal injury occurs without the formation of new blood vessels; however, neovascularization may be induced during corneal wound healing when the balance between proangiogenic and antiangiogenic mediators is disrupted to favor angiogenesis. Matrix metalloproteinases (MMPs), which are key factors in extracellular matrix remodeling and angiogenesis, contribute to the maintenance of this balance, and in pathologic instances, can contribute to its disruption. Here, we elaborate on the facilitative role of MMPs, specifically MMP-14, in corneal neovascularization. MMP-14 is a transmembrane MMP that is critically involved in extracellular matrix proteolysis, exosome transport, and cellular migration and invasion, processes that are critical for angiogenesis. To aid in developing efficacious therapies that promote healing without neovascularization, it is important to understand and further investigate the complex pathways related to MMP-14 signaling, which can also involve vascular endothelial growth factor, basic fibroblast growth factor, Wnt/β-catenin, transforming growth factor, platelet-derived growth factor, hepatocyte growth factor or chemokines, epidermal growth factor, prostaglandin E2, thrombin, integrins, Notch, Toll-like receptors, PI3k/Akt, Src, RhoA/RhoA kinase, and extracellular signal-related kinase. The involvement and potential contribution of these signaling molecules or proteins in neovascularization are the focus of the present review.
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Affiliation(s)
- Jin-Hong Chang
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Yu-Hui Huang
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Christy M Cunningham
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Kyu-Yeon Han
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Michael Chang
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Motoharu Seiki
- Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Zhongjun Zhou
- Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Dimitri T Azar
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois, USA.
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8
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Batra H, Antony VB. Pleural mesothelial cells in pleural and lung diseases. J Thorac Dis 2015; 7:964-80. [PMID: 26150910 DOI: 10.3978/j.issn.2072-1439.2015.02.19] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2014] [Accepted: 02/11/2015] [Indexed: 12/12/2022]
Abstract
During development, the mesoderm maintains a complex relationship with the developing endoderm giving rise to the mature lung. Pleural mesothelial cells (PMCs) derived from the mesoderm play a key role during the development of the lung. The pleural mesothelium differentiates to give rise to the endothelium and smooth muscle cells via epithelial-to-mesenchymal transition (EMT). An aberrant recapitulation of such developmental pathways can play an important role in the pathogenesis of disease processes such as idiopathic pulmonary fibrosis (IPF). The PMC is the central component of the immune responses of the pleura. When exposed to noxious stimuli, it demonstrates innate immune responses such as Toll-like receptor (TLR) recognition of pathogen associated molecular patterns as well as causes the release of several cytokines to activate adaptive immune responses. Development of pleural effusions occurs due to an imbalance in the dynamic interaction between junctional proteins, n-cadherin and β-catenin, and phosphorylation of adherens junctions between PMCs, which is caused in part by vascular endothelial growth factor (VEGF) released by PMCs. PMCs play an important role in defense mechanisms against bacterial and mycobacterial pleural infections, and in pathogenesis of malignant pleural effusion, asbestos related pleural disease and malignant pleural mesothelioma. PMCs also play a key role in the resolution of inflammation, which can occur with or without fibrosis. Fibrosis occurs as a result of disordered fibrin turnover and due to the effects of cytokines such as transforming growth factor-β, platelet-derived growth factor (PDGF), and basic fibroblast growth factor; which are released by PMCs. Recent studies have demonstrated a role for PMCs in the pathogenesis of IPF suggesting their potential as a cellular biomarker of disease activity and as a possible therapeutic target. Pleural-based therapies targeting PMCs for treatment of IPF and other lung diseases need further exploration.
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Affiliation(s)
- Hitesh Batra
- Division of Pulmonary, Allergy & Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham Birmingham, AL, USA
| | - Veena B Antony
- Division of Pulmonary, Allergy & Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham Birmingham, AL, USA
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9
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Deng XB, Xiao L, Wu Y, Jin F, Mossman B, Testa JR, Xiao GH. Inhibition of mesothelioma cancer stem-like cells with adenovirus-mediated NK4 gene therapy. Int J Cancer 2014; 137:481-90. [PMID: 25501304 DOI: 10.1002/ijc.29391] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 11/24/2014] [Indexed: 02/05/2023]
Abstract
Malignant mesothelioma (MM) is a highly invasive and chemoresistant malignancy induced by asbestos fibers. NK4, a hepatocyte growth factor antagonist and angiogenesis inhibitor, consists of the N-terminal hairpin domain and four kringle domains of the α-chain of hepatocyte growth factor. The therapeutic potential of NK4 has been demonstrated in a variety of tumor types. However, the mechanisms by which NK4 inhibits tumor growth have not been well delineated. In this study, it is shown that the NK4 adenovirus (Ad-NK4) potently inhibits cell viability, invasiveness and tumorigenicity of human MM cells. Significantly, this study demonstrates for the first time that Ad-NK4 inhibits cancer stem-like cell (CSC) properties as assessed by spheroid formation assay, side population analysis and flow cytometric sorting of CD24 cells. In addition to inhibiting phosphorylation of Met and AKT, Ad-NK4 markedly suppressed the active form of β-catenin, a key mediator of both Wnt and AKT pathways. It is further demonstrated that expression of NK4 suppresses β-catenin nuclear localization and transcriptional activity. Intriguingly, the expression levels of Oct4 and Myc, two critical stem cell factors and downstream targets of β-catenin, were also diminished by Ad-NK4. Furthermore, the strong antitumor effect of NK4 was found to be linked to its ability to inhibit CSCs as revealed by immunohistochemical examination of tumor specimens from a mouse xenograft model of human MM. These findings suggest that NK4 acts as a CSC inhibitor by impeding Met/AKT/β-catenin signaling and holds promise for achieving durable therapeutic responses in MM by constraining the CSC component of these aggressive tumors.
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Affiliation(s)
- Xu-Bin Deng
- Cancer Institute, Southern Medical University, Guangzhou, China
| | - Li Xiao
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA
| | - Yue Wu
- Cancer Institute, Southern Medical University, Guangzhou, China
| | - Fang Jin
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA
| | - Brooke Mossman
- Department of Pathology, University of Vermont College of Medicine, Burlington, VT
| | - Joseph R Testa
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA
| | - Guang-Hui Xiao
- Cancer Institute, Southern Medical University, Guangzhou, China.,Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA
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10
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Gaudino G, Yang H, Carbone M. HGF/Met Signaling Is a Key Player in Malignant Mesothelioma Carcinogenesis. Biomedicines 2014; 2:327-344. [PMID: 28548074 PMCID: PMC5344271 DOI: 10.3390/biomedicines2040327] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Revised: 11/03/2014] [Accepted: 11/06/2014] [Indexed: 12/25/2022] Open
Abstract
Malignant mesothelioma (MM) is a highly aggressive cancer related to asbestos or erionite exposure and resistant to current therapies. Hepatocyte Growth Factor (HGF) and its tyrosine kinase receptor Met regulate cell growth, survival, motility/migration, and invasion. HGF and Met are expressed in MM cells, suggesting that the HGF/Met signaling plays a role in development and progression of this tumor, by autocrine and/or paracrine mechanisms. Upregulation and ligand-independent activation of Met, which is under suppressive control of miR-34 family members, correlate with enhanced invasion, migration and metastatic potential in several cancers, including MM. Moreover, Simian Virus 40 (SV40) Tag expression also induces a HGF autocrine circuit in an Rb-dependent manner in human mesothelial cells (HM) and possibly other cell types, enhancing cell adhesion, invasion and angiogenesis. The resulting activation of Met causes HM transformation and cell cycle progression, and contributes to virus particle assembling and infection of adjacent cells. The constitutive activation of Met, frequently occurring in MM, has been successfully targeted in preclinical models of MM. In conclusion, Met expression, activation state, subcellular localization and also HGF co-receptors expression, such as CD44, have clinical relevance for novel targeted therapies in a cancer for which no effective treatment is currently available.
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Affiliation(s)
- Giovanni Gaudino
- University of Hawai'i Cancer Center, 701 Ilalo Street, Honolulu, HI 96813, USA.
| | - Haining Yang
- University of Hawai'i Cancer Center, 701 Ilalo Street, Honolulu, HI 96813, USA.
| | - Michele Carbone
- University of Hawai'i Cancer Center, 701 Ilalo Street, Honolulu, HI 96813, USA.
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11
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Zhou S, Liu L, Li H, Eilers G, Kuang Y, Shi S, Yan Z, Li X, Corson JM, Meng F, Zhou H, Sheng Q, Fletcher JA, Ou WB. Multipoint targeting of the PI3K/mTOR pathway in mesothelioma. Br J Cancer 2014; 110:2479-88. [PMID: 24762959 PMCID: PMC4021537 DOI: 10.1038/bjc.2014.220] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Revised: 03/20/2014] [Accepted: 03/27/2014] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Mesothelioma is a notoriously chemotherapy-resistant neoplasm, as is evident in the dismal overall survival for patients with those of asbestos-associated disease. We previously demonstrated co-activation of multiple receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR), MET, and AXL in mesothelioma cell lines, suggesting that these kinases could serve as novel therapeutic targets. Although clinical trials have not shown activity for EGFR inhibitors in mesothelioma, concurrent inhibition of various activated RTKs has pro-apoptotic and anti-proliferative effects in mesothelioma cell lines. Thus, we hypothesised that a coordinated network of multi-RTK activation contributes to mesothelioma tumorigenesis. METHODS Activation of PI3K/AKT/mTOR, Raf/MAPK, and co-activation of RTKs were evaluated in mesotheliomas. Effects of RTK and downstream inhibitors/shRNAs were assessed by measuring mesothelioma cell viability/growth, apoptosis, activation of signalling intermediates, expression of cell-cycle checkpoints, and cell-cycle alterations. RESULTS We demonstrate activation of the PI3K/AKT/p70S6K and RAF/MEK/MAPK pathways in mesothelioma, but not in non-neoplastic mesothelial cells. The AKT activation, but not MAPK activation, was dependent on coordinated activation of RTKs EGFR, MET, and AXL. In addition, PI3K/AKT/mTOR pathway inhibition recapitulated the anti-proliferative effects of concurrent inhibition of EGFR, MET, and AXL. Dual targeting of PI3K/mTOR by BEZ235 or a combination of RAD001 and AKT knockdown had a greater effect on mesothelioma proliferation and viability than inhibition of individual activated RTKs or downstream signalling intermediates. Inhibition of PI3K/AKT was also associated with MDM2-p53 cell-cycle regulation. CONCLUSIONS These findings show that PI3K/AKT/mTOR is a crucial survival pathway downstream of multiple activated RTKs in mesothelioma, underscoring that PI3K/mTOR is a compelling target for therapeutic intervention.
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Affiliation(s)
- S Zhou
- 1] Zhejiang Provincial Key Laboratory of Applied Enzymology, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, China [2] Department of Bioengineering, College of Biology and Chemical Engineering, Jiaxing University, Jiaxing, China
| | - L Liu
- Zhejiang Provincial Key Laboratory of Applied Enzymology, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, China
| | - H Li
- Zhejiang Provincial Key Laboratory of Applied Enzymology, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, China
| | - G Eilers
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Y Kuang
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China
| | - S Shi
- Zhejiang Provincial Key Laboratory of Applied Enzymology, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, China
| | - Z Yan
- Zhejiang Provincial Key Laboratory of Applied Enzymology, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, China
| | - X Li
- Zhejiang Provincial Key Laboratory of Applied Enzymology, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, China
| | - J M Corson
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - F Meng
- Zhejiang Provincial Key Laboratory of Applied Enzymology, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, China
| | - H Zhou
- Zhejiang Provincial Key Laboratory of Applied Enzymology, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, China
| | - Q Sheng
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China
| | - J A Fletcher
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - W-B Ou
- 1] Zhejiang Provincial Key Laboratory of Applied Enzymology, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, China [2] Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA [3] Department of Biochemistry and Molecular Biology, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China
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Farina AR, Mackay AR. Gelatinase B/MMP-9 in Tumour Pathogenesis and Progression. Cancers (Basel) 2014; 6:240-96. [PMID: 24473089 PMCID: PMC3980597 DOI: 10.3390/cancers6010240] [Citation(s) in RCA: 154] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Revised: 01/20/2014] [Accepted: 01/21/2014] [Indexed: 12/14/2022] Open
Abstract
Since its original identification as a leukocyte gelatinase/type V collagenase and tumour type IV collagenase, gelatinase B/matrix metalloproteinase (MMP)-9 is now recognised as playing a central role in many aspects of tumour progression. In this review, we relate current concepts concerning the many ways in which gelatinase B/MMP-9 influences tumour biology. Following a brief outline of the gelatinase B/MMP-9 gene and protein, we analyse the role(s) of gelatinase B/MMP-9 in different phases of the tumorigenic process, and compare the importance of gelatinase B/MMP-9 source in the carcinogenic process. What becomes apparent is the importance of inflammatory cell-derived gelatinase B/MMP-9 in tumour promotion, early progression and triggering of the "angiogenic switch", the integral relationship between inflammatory, stromal and tumour components with respect to gelatinase B/MMP-9 production and activation, and the fundamental role for gelatinase B/MMP-9 in the formation and maintenance of tumour stem cell and metastatic niches. It is also apparent that gelatinase B/MMP-9 plays important tumour suppressing functions, producing endogenous angiogenesis inhibitors, promoting inflammatory anti-tumour activity, and inducing apoptosis. The fundamental roles of gelatinase B/MMP-9 in cancer biology underpins the need for specific therapeutic inhibitors of gelatinase B/MMP-9 function, the use of which must take into account and substitute for tumour-suppressing gelatinase B/MMP-9 activity and also limit inhibition of physiological gelatinase B/MMP-9 function.
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Affiliation(s)
- Antonietta Rosella Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, Via Vetoio, Coppito 2, L'Aquila 67100, Italy.
| | - Andrew Reay Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, Via Vetoio, Coppito 2, L'Aquila 67100, Italy.
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13
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Roomi MW, Kalinovsky T, Rath M, Niedzwiecki A. In vitro modulation of MMP-2 and MMP-9 in pediatric human sarcoma cell lines by cytokines, inducers and inhibitors. Int J Oncol 2013; 44:27-34. [PMID: 24190483 PMCID: PMC3867366 DOI: 10.3892/ijo.2013.2159] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Accepted: 10/08/2013] [Indexed: 11/05/2022] Open
Abstract
The highly aggressive pediatric sarcomas are characterized by high levels of matrix metalloproteinase (MMP)-2 and MMP-9, which play crucial roles in tumor invasion and metastasis by degradation of the extracellular membrane leading to cancer cell spread to distal organs. We examined the effects of cytokines, mitogens, inducers and inhibitors on MMP-2 and -9 expression in osteosarcoma (U2OS) and rhabdomyosarcoma (RD). The selected compounds included natural cytokines and growth factors, as well as chemical compounds applied in therapy of sarcoma and natural compounds that have demonstrated anticancer therapeutic potential. These cell lines were cultured in their respective media to near confluence and the cells were washed with PBS and incubated in serum-free medium with various concentrations of several cytokines, mitogens and inhibitors. After 24 h the media were removed and analyzed for MMP-2 and -9 by gelatinase zymography and quantitated by densitometry. Osteosarcoma and rhabdomyosarcoma showed bands corresponding to MMP-2 and -9 with dose-dependent enhancement of MMP-9 with phorbol 12-myristate 13-acetate (PMA) treatment. Tumor necrosis factor-α, interleukin-1β and LPS enhanced osteosarcoma U2OS MMP-9 secretion but had no effect on MMP-2 secretion. Tumor necrosis factor-α stimulated rhabdomyosarcoma MMP-2 expression, but had no effect on MMP-9 secretion. Doxycycline, epigallocatechin gallate, nutrient mixture (NM), actinomycin-D, cyclohex-amide, retinoic acid and dexamethasone inhibited MMP-2 and -9 in U2OS osteosarcoma cells. PMA-treated RD cells showed dose-response inhibition of MMP-9 by doxycycline and epigallocatechin gallate and both MMPs by NM. Dexamethasone and actinomycin-D showed inhibition of MMP-2 secretion of RD cells. Our results show that cytokines, mitogens and inducers show variable upregulation of U2OS osteosarcoma and RD rhabdomyosarcoma MMP-2 and -9 secretion, and inhibitors demonstrate downregulation under stimulatory conditions, suggesting the application of these agents for the development of effective therapies in pediatric sarcomas.
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Affiliation(s)
- M W Roomi
- Dr Rath Research Institute, Santa Clara, CA 95050, USA
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Roomi MW, Kalinovsky T, Monterrey J, Rath M, Niedzwiecki A. In vitro modulation of MMP-2 and MMP-9 in adult human sarcoma cell lines by cytokines, inducers and inhibitors. Int J Oncol 2013; 43:1787-98. [PMID: 24085323 PMCID: PMC3834263 DOI: 10.3892/ijo.2013.2113] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Accepted: 09/13/2013] [Indexed: 11/15/2022] Open
Abstract
The highly aggressive adult sarcomas are characterized by high levels of matrix metalloproteinase (MMP)-2 and -9, which play crucial roles in tumor invasion and metastasis by degradation of the extracellular membrane leading to cancer cell spread to distal organs. We examined the effect of cytokines, mitogens, inducers and inhibitors on MMP-2 and MMP-9 secretion in chondrosarcoma (SW-1353), fibrosarcoma (HT-1080), liposarcoma (SW-872) and synovial sarcoma (SW-982) cell lines. The selected compounds included natural cytokines and growth factors, as well as chemical compounds applied in therapy of sarcoma and natural compounds that have demonstrated anticancer therapeutic potential. MMP-2 and MMP-9 secretions were analyzed by gelatinase zymography following 24-h exposure to the tested agents and quantitated by densitometry. Fibrosarcoma, chondrosarcoma, liposarcoma and synovial sarcoma showed bands corresponding to MMP-2 and MMP-9 with dose-dependent enhancement of MMP-9 with phorbol 12-myristate 13-acetate (PMA) treatment. In chondrosarcoma cells, tumor necrosis factor (TNF)-α had a stimulatory effect on MMP-9 and insignificant effect on MMP-2 and interleukin (IL)-1β stimulated MMP-9 and MMP-2. In fibrosarcoma and liposarcoma cells, TNF-α had a profound stimulatory effect on MMP-9, but no effect on MMP-2 and in synovial sarcoma an inhibitory effect on MMP-2 and no effect on MMP-9. IL-1β had a slight inhibitory effect on fibrosarcoma, liposarcoma and synovial sarcoma MMP-2 and MMP-9 except for MMP-9 in synovial sarcoma which showed slight stimulation. Lipopolysaccharide (LPS) stimulated expression of MMP-2 in fibrosarcoma and chondrosarcoma while inhibited it in liposarcoma. Doxycycline, epigallocatechin gallate and the nutrient mixture inhibited MMP-2 and MMP-9 in all cell lines. Actinomycin-D, cyclohexamide, retinoic acid, and dexamethasone inhibited MMP-2 and -9 in chondrosarcoma and fibrosarcoma cells. Our results show that cytokines, mitogens, inducers and inhibitors have an up or down regulatory effect on MMP-2 and MMP-9 expression in adult sarcoma cell lines, suggesting these agents may be effective strategies to treat these cancers.
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Affiliation(s)
- M W Roomi
- Dr. Rath Research Institute, Santa Clara, CA 95050, USA
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Overexpression of EPH Receptor B2 in Malignant Mesothelioma Correlates with Oncogenic Behavior. J Thorac Oncol 2013; 8:1203-11. [DOI: 10.1097/jto.0b013e31829ceb6a] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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16
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Luraghi P, Schelter F, Krüger A, Boccaccio C. The MET Oncogene as a Therapeutical Target in Cancer Invasive Growth. Front Pharmacol 2012; 3:164. [PMID: 22973229 PMCID: PMC3438853 DOI: 10.3389/fphar.2012.00164] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Accepted: 08/21/2012] [Indexed: 01/30/2023] Open
Abstract
The MET proto-oncogene, encoding the tyrosine kinase receptor for Hepatocyte Growth Factor (HGF) regulates invasive growth, a genetic program that associates control of cell proliferation with invasion of the extracellular matrix and protection from apoptosis. Physiologically, invasive growth takes place during embryonic development, and, in post-natal life, in wound healing and regeneration of several tissues. The MET oncogene is overexpressed and/or genetically mutated in many tumors, thereby sustaining pathological invasive growth, a prerequisite for metastasis. MET is the subject of intense research as a target for small molecule kinase inhibitors and, together with its ligand HGF, for inhibitory antibodies. The tight interplay of MET with the protease network has unveiled mechanisms to be exploited to achieve effective inhibition of invasive growth.
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Affiliation(s)
- Paolo Luraghi
- Division of Experimental Clinical Molecular Oncology, IRCC – Institute for Cancer Research and Treatment, University of Turin Medical SchoolCandiolo, Italy
| | - Florian Schelter
- Klinikum rechts der Isar der Technischen Universität München, Institut für Experimentelle Onkologie und TherapieforschungMünchen, Germany
| | - Achim Krüger
- Klinikum rechts der Isar der Technischen Universität München, Institut für Experimentelle Onkologie und TherapieforschungMünchen, Germany
| | - Carla Boccaccio
- Division of Experimental Clinical Molecular Oncology, IRCC – Institute for Cancer Research and Treatment, University of Turin Medical SchoolCandiolo, Italy
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Plasma Cell Membrane Localization of c-MET Predicts Longer Survival in Patients with Malignant Mesothelioma: A Series of 157 Cases from the MESOPATH Group. J Thorac Oncol 2012; 7:599-606. [DOI: 10.1097/jto.0b013e3182417da5] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Murakami A, Tabata C, Tabata R, Okuwa H, Nakano T. Clinical role of pleural effusion MMP-3 levels in malignant pleural mesothelioma. Oncol Lett 2011; 3:581-585. [PMID: 22740956 DOI: 10.3892/ol.2011.536] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2011] [Accepted: 11/25/2011] [Indexed: 12/29/2022] Open
Abstract
Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin associated with asbestos exposure. MPM exhibits a limited response to conventional chemotherapy and radiotherapy. This, early diagnosis of MPM is essential. Malignant tumor progression requires the destruction of the basement membrane, which is constructed from extracellular matrix (ECM) materials. Various types of human tumor cells are reported to produce ECM-degrading proteases that are important in tumor progression. Among this group of proteolytic enzymes, matrix metalloproteinases (MMPs) are thought to be important due to their wide degrading function. We investigated the pleural effusion MMP-3 levels of patients with MPM and compared them with those of a population with non-malignant pleuritis or lung cancer involving malignant pleural effusion. The pleural effusion MMP-3 concentrations of 52 MPM patients and 67 non-MPM patients were measured. The results showed that the MPM patients had significantly higher pleural effusion MMP-3 levels than the population with non-malignant pleuritis. The overall survival of the MPM patients with lower pleural effusion MMP-3 levels was longer than that of patients with higher pleural effusion MMP-3 levels. Our data therefore suggest a clinical role of pleural effusion MMP-3 levels in malignant pleural mesothelioma.
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Affiliation(s)
- Aki Murakami
- Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan
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Targeted inhibition of multiple receptor tyrosine kinases in mesothelioma. Neoplasia 2011; 13:12-22. [PMID: 21245936 PMCID: PMC3022424 DOI: 10.1593/neo.101156] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2010] [Revised: 09/24/2010] [Accepted: 09/28/2010] [Indexed: 12/14/2022] Open
Abstract
The receptor tyrosine kinases (RTKs) epidermal growth factor receptor (EGFR) and MET are activated in subsets of mesothelioma, suggesting that these kinases might represent novel therapeutic targets in this notoriously chemotherapy-resistant cancer. However, clinical trials have shown little activity for EGFR inhibitors in mesothelioma. Despite the evidence for RTK activation in mesothelioma pathogenesis, it is unclear whether transforming activity is dependent on an individual kinase oncoprotein or the coordinated activity of multiple kinases. Using phospho-RTK and immunoblot assays, we herein demonstrate activation of multiple RTKs (EGFR, MET, AXL, and ERBB3) in individual mesothelioma cell lines but not in normal mesothelioma cells. Inhibition of mesothelioma multi-RTK signaling was accomplished using combinations of RTK direct inhibitors or by inhibition of the RTK chaperone, heat shock protein 90 (HSP90). Multi-RTK inhibition by the HSP90 inhibitor 17-allyloamino-17-demethoxygeldanamycin (17-AAG) had a substantially greater effect on mesothelioma proliferation and survival compared with inhibition of individual activated RTKs. HSP90 inhibition also suppressed phosphorylation of downstream signaling intermediates (AKT, mitogen-activated protein kinase, and S6); upregulated the p53, p21, and p27 cell cycle checkpoints; induced G(2) phase arrest; induced caspase 3/7 activity; and led to an increase in the sub-G(1) apoptotic population. These compelling proapoptotic and antiproliferative responses indicate that HSP90 inhibition warrants clinical evaluation as a novel therapeutic strategy in mesothelioma.
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Suzuki Y, Sakai K, Ueki J, Xu Q, Nakamura T, Shimada H, Nakamura T, Matsumoto K. Inhibition of Met/HGF receptor and angiogenesis by NK4 leads to suppression of tumor growth and migration in malignant pleural mesothelioma. Int J Cancer 2010; 127:1948-57. [PMID: 20104519 DOI: 10.1002/ijc.25197] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
NK4 exhibits two distinct biological actions: antagonistic inhibition of hepatocyte growth factor (HGF) through binding to the Met/HGF receptor, and antiangiogenic action through binding to perlecan. Here, the anti-tumor effect of NK4 on malignant pleural mesothelioma was investigated. Of the 7 human malignant mesothelioma cell lines (ACC-Meso-1, ACC-Meso-4, EHMES-1, EHMES-10, H28, H2052 and JMN-1B), only EHMES-10 cells formed subcutaneous tumors when implanted into mice. For EHMES-10 cells, HGF facilitated invasion of the cells in collagen gel, whereas NK4 and neutralizing anti-HGF antibody suppressed the HGF-induced invasion. In addition, NK4 but not anti-HGF antibody suppressed proliferation of EHMES-10 cells in collagen, suggesting that the suppression by NK4 was independent of the HGF-Met pathway. In the subcutaneous tumor model, recombinant adenovirus-mediated intratumoral expression of NK4 inhibited tumor growth, while the invasive characteristic of tumor cells was not observed. Analysis of Met receptor tyrosine phosphorylation, proliferation, apoptosis and blood vessels in the tumor tissues indicated that the inhibitory effect of NK4 expression might be primarily caused by the inhibition of tumor angiogenesis. In all the 7 mesothelioma lines, HGF stimulated Met tyrosine phosphorylation, and this was associated with enhanced cell migration. HGF-dependent Met activation and migration were inhibited by NK4. Since malignant pleural mesothelioma represents an aggressive neoplasm characterized by extensive invasive growth, suppression of invasive growth has therapeutic value. Thus, the simultaneous inhibition of the HGF-Met pathway and angiogenesis by NK4 for treatment of malignant pleural mesothelioma is significant, particularly to attenuate migration and invasive growth.
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Affiliation(s)
- Yoshinori Suzuki
- Division of Molecular Regenerative Medicine, Department of Biochemistry and Molecular Biology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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Takeuchi T, Iwasaki S, Miyazaki J, Nozaki Y, Takahashi M, Ono M, Saibara T, Furihata M. Matrix metalloproteinase-1 expression in splenic angiosarcoma metastasizing to the serous membrane. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2010; 3:634-639. [PMID: 20661412 PMCID: PMC2907126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 05/26/2010] [Accepted: 06/09/2010] [Indexed: 05/29/2023]
Abstract
Angiosarcoma involving the serous membrane may mimic mesothelioma; therefore, the term "pseudomesotheliomatous angiosarcoma" has been suggested for this entity. However, the pathogenesis of pseudomesotheliomatous angiosarcoma remains unclear. Here, we report an autopsy case of splenic angiosarcoma, which systemically metastasized to the serous membrane of both the peritoneum and pleura, closely resembling a mesothelioma. The spindle-shaped tumor cells exhibited marked invasion of the lymphatic vessels and invaded the serous membrane causing thickening of the fibrous tissues like desmoplastic mesothelioma. In the present case, immunohistochemical staining showed that the tumor expressed not only the endothelial cell markers, such as CD31, vascular endothelial growth factor receptor 3, and podoplanin (D2-40), but also matrix metalloproteinase-1 (also known as collagenase-1), which is known to increase the invasiveness of mesothelioma cells. MMP-1 expression was not observed in the other cases of angiosarcoma, examined. This tumor might systemically metastasize to the serous membrane via the lymphatic route and might generate the fibrous stroma aided by the matrix metalloproteinase-1.
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Affiliation(s)
- Tamotsu Takeuchi
- Department of Pathology, Kochi Medical School, Nankoku, Kochi, Japan.
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Miselis NR, Lau BW, Wu Z, Kane AB. Kinetics of host cell recruitment during dissemination of diffuse malignant peritoneal mesothelioma. CANCER MICROENVIRONMENT : OFFICIAL JOURNAL OF THE INTERNATIONAL CANCER MICROENVIRONMENT SOCIETY 2010; 4:39-50. [PMID: 21505561 PMCID: PMC3047623 DOI: 10.1007/s12307-010-0048-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2010] [Accepted: 06/07/2010] [Indexed: 12/14/2022]
Abstract
UNLABELLED Diffuse malignant mesothelioma is an aggressive tumor which displays a median survival of 11.2 months and a 5-year survival of less than 5% emphasizing the need for more effective treatments. This study uses an orthotopic model of malignant mesothelioma established in syngeneic, immunocompetent C57Bl/6 mice which produce malignant ascites and solid tumors that accurately replicate the histopathology of the human disease. Host stromal and immune cell accumulation within malignant ascites and solid tumors was determined using immunofluorescent labeling with confocal microscopy and fluorescence-activated cell sorting. An expression profile of cytokines and chemokines was produced using quantitative real-time PCR arrays. Tumor spheroids and solid tumors show progressive growth and infiltration with host stromal and immune cells including macrophages, endothelial cells, CD4(+) and CD8(+) lymphocytes, and a novel cell type, myeloid derived suppressor cells (MDSCs). The kinetics of host cell accumulation and inflammatory mediator expression within the tumor ascites divides tumor progression into two distinct phases. The first phase is characterized by progressive macrophage and T lymphocyte recruitment, with a cytokine profile consistent with regulatory T lymphocytes differentiation and suppression of T cell function. The second phase is characterized by decreased expression of macrophage chemotactic and T-cell regulating factors, an increase in MDSCs, and increased expression of several cytokines which stimulate differentiation of MDSCs. This cellular and expression profile suggests a mechanism by which host immune cells promote diffuse malignant mesothelioma progression. ELECTRONIC SUPPLEMENTARY MATERIAL The online version of this article (doi:10.1007/s12307-010-0048-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Nathan R. Miselis
- Department of Pathology and Laboratory Medicine, Brown University, Providence, RI USA
- Massachusetts General Hospital Cancer Center, Boston, MA 02115 USA
| | - Bonnie W. Lau
- Department of Pathology and Laboratory Medicine, Brown University, Providence, RI USA
- Pathobiology Graduate Program, Brown University, Providence, RI USA
| | - Zhijin Wu
- Center for Statistical Sciences, Brown University, Providence, RI USA
| | - Agnes B. Kane
- Department of Pathology and Laboratory Medicine, Brown University, Providence, RI USA
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Davidson B. New diagnostic and molecular characteristics of malignant mesothelioma. Ultrastruct Pathol 2009; 32:227-40. [PMID: 19117264 DOI: 10.1080/01913120802454298] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Malignant mesothelioma is a primary cancer of the serosal cavities, an anatomic site that is also frequently affected by metastatic disease, predominantly from primary carcinomas of the lung, breast, and ovary. Advances in immunohistochemistry have resulted in improved diagnostic sensitivity and specificity in the differential diagnosis between metastatic adenocarcinoma and malignant mesothelioma in both cytological and histological material. Recently, the author's group applied high throughput technology to the identification of new markers that may aid in differentiating malignant mesothelioma from ovarian and peritoneal serous carcinoma, tumors with closely related histogenesis and antigenic profile. In addition to the improved tools available for serosal cancer diagnosis, knowledge regarding the biology of malignant mesothelioma has been accumulating in recent years. This review presents current data regarding the diagnostic and biological aspects of malignant mesothelioma.
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Affiliation(s)
- Ben Davidson
- Division of Pathology, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, Norway.
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Amati M, Tomasetti M, Scartozzi M, Mariotti L, Alleva R, Pignotti E, Borghi B, Valentino M, Governa M, Neuzil J, Santarelli L. Profiling Tumor-Associated Markers for Early Detection of Malignant Mesothelioma: An Epidemiologic Study. Cancer Epidemiol Biomarkers Prev 2008; 17:163-70. [DOI: 10.1158/1055-9965.epi-07-0607] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Davidson B. Expression of cancer-associated molecules in malignant mesothelioma. Biomark Insights 2007; 2:173-84. [PMID: 19662202 PMCID: PMC2717840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Malignant mesothelioma (MM) is a malignant tumor derived from mesothelial cells, native cells of the body cavities. Exposure to asbestos is the most strongly established etiologic factor, predominantly for the most common disease form, pleural mesothelioma. The pathogenesis of MM involves the accumulation of extensive cytogenetic changes, as well as cancer-related phenotypic alterations that facilitate tumor cell survival, invasion and metastasis. This review presents current knowledge regarding the biological characteristics of this disease that are linked to the so-called hallmarks of cancer. In addition, data suggesting that the anatomic site (solid tumor vs. effusion) affects the expression of metastasis-associated and regulatory molecules in MM are presented. Finally, recent work in which high-throughput methodology has been applied to MM research is reviewed. The data obtained in the reviewed research may aid in defining new prognostic markers and therapeutic targets for this aggressive disease in the future.
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Affiliation(s)
- Ben Davidson
- Correspondence: Dr. Ben Davidson, Department of Pathology, Rikshospitalet-Radiumhospitalet Medical Center, Montebello N-0310 Oslo, Norway. Tel: 47-22934871; Fax: 47-22508554;
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Abstract
Malignant mesothelioma (MM) is a malignant tumor derived from mesothelial cells, native cells of the body cavities. Exposure to asbestos is the most strongly established etiologic factor, predominantly for the most common disease form, pleural mesothelioma. The pathogenesis of MM involves the accumulation of extensive cytogenetic changes, as well as cancer-related phenotypic alterations that facilitate tumor cell survival, invasion and metastasis. This review presents current knowledge regarding the biological characteristics of this disease that are linked to the so-called hallmarks of cancer. In addition, data suggesting that the anatomic site (solid tumor vs. effusion) affects the expression of metastasis-associated and regulatory molecules in MM are presented. Finally, recent work in which high-throughput methodology has been applied to MM research is reviewed. The data obtained in the reviewed research may aid in defining new prognostic markers and therapeutic targets for this aggressive disease in the future.
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Affiliation(s)
- Ben Davidson
- Department of Pathology, Rikshospitalet-Radiumhospitalet Medical Center, Montebello N-0310 Oslo, Norway
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Alexandrakis MG, Sfiridaki A, Miyakis S, Pappa C, Kandidaki E, Alegakis A, Margioris AN. Relationship between serum levels of vascular endothelial growth factor, hepatocyte growth factor and matrix metalloproteinase-9 with biochemical markers of bone disease in multiple myeloma. Clin Chim Acta 2006; 379:31-5. [PMID: 17234170 DOI: 10.1016/j.cca.2006.11.024] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2006] [Revised: 11/29/2006] [Accepted: 11/29/2006] [Indexed: 10/23/2022]
Abstract
BACKGROUND Multiple myeloma is characterized by accumulation of plasma cells in the bone marrow, with osteolysis and increased marrow angiogenesis. We studied molecules involved in angiogenesis (MMP-9, HGF, VEGF) in relation to disease stage, extent of bone destruction, and markers of bone turnover (Ntx and PICP). METHODS MMP-9, HGF, VEGF were measured in the serum of 42 newly diagnosed myeloma patients and 24 controls with commercial ELISA kits. Urinary levels of Ntx were measured by ELISA, and serum PICP with RIA. Extent of radiological bone disease was graded into low and high score. Stage was estimated according to the Durie-Salmon criteria. RESULTS HGF, VEGF and Ntx were higher in patients than controls (p<0.001). MMP-9 and PICP did not differ between patients and controls. HGF, VEGF, MMP-9 and Ntx increased significantly with disease stage (I to III, p<0.001) and PICP decreased significantly with advancing stage (p<0.05). There was a positive correlation between HGF and MMP-9 (r: 0.36, p<0.01), VEGF and MMP-9 (r: 0.38, p<0.01), Ntx and MMP-9 (r: 0.39, p<0.01) and an inverse correlation between PICP and MMP-9 (r: -0.66, p<0.0001). CONCLUSIONS Angiogenesis and bone destruction are closely interrelated in myeloma, and cytokine levels (MMP-9, VEGF and HGF) may be useful in monitoring progression.
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Abstract
PURPOSE OF REVIEW Pleural fibrosis is a double-edged sword in clinical settings. Successful induction of pleural fibrosis is the basis of therapeutic pleurodesis. On the other hand, pleural septations and fibrosis are undesirable outcomes in pleural infection and fibrothoraces. The significance of growth factors in the pathogenesis of pleural fibrosis has become increasingly apparent. RECENT FINDINGS Recent findings have indicated that transforming growth factor beta is a key mediator of pleural fibrosis and demonstrated the therapeutic potential of both transforming growth factor beta itself and transforming growth factor beta inhibitors. Basic fibroblast growth factor has been highlighted as a key factor in successful pleurodesis, and in the formation of pleural effusions. Vascular endothelial growth factor inhibition has been shown to decrease pleural fibrosis in vivo. By contrast, hepatocyte growth factor stimulates non-fibrotic healing, while inhibition increases fibrosis. SUMMARY The actions of the growth factors, and their inhibitors, are potentially and/or currently applicable in a clinical setting. Understanding the biology of these growth factors may allow therapeutic manipulation of these cytokines to create pleurodesis or to inhibit pleural (and peritoneal) adhesion/fibrosis.
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Affiliation(s)
- Steven E Mutsaers
- Asthma, Allergy & Respiratory Research Institute, Department of Medicine, University of Western Australia, Perth, Australia
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Yeh MW, Rougier JP, Park JW, Duh QY, Wong M, Werb Z, Clark OH. Differentiated thyroid cancer cell invasion is regulated through epidermal growth factor receptor-dependent activation of matrix metalloproteinase (MMP)-2/gelatinase A. Endocr Relat Cancer 2006; 13:1173-83. [PMID: 17158762 PMCID: PMC2574514 DOI: 10.1677/erc.1.01226] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Mechanisms of invasion in thyroid cancer remain poorly understood. We hypothesized that signaling via the epidermal growth factor receptor (EGFR) stimulates thyroid cancer cell invasion by altering the expression and cleavage of matrix metalloproteinases (MMPs). Papillary and follicular carcinoma cell lines were treated with EGF, the EGFR tyrosine kinase inhibitor AG1478, and the MMP inhibitors GM-6001 and Col-3. Flow cytometry was used to detect EGFR. In vitro invasion assays, gelatin zymography, and quantitative reverse transcription-PCR were used to assess the changes in invasive behavior and MMP expression and activation. All cell lines were found to overexpress functional EGFR. EGF stimulated invasion by thyroid cancer cells up to sevenfold (P<0.0001), a process that was antagonized completely by AG1478 and Col-3, partially by GM-6001, but not by the serine protease inhibitor aprotinin. EGF upregulated expression of MMP-9 (2.64- to 8.89-fold, P<0.0001) and membrane type-1 MMP (MT1-MMP, 1.97- to 2.67-fold, P<0.0001). This effect was blocked completely by AG1478 and partially by Col-3. The activation of MMP-2 paralleled MT1-MMP expression. We demonstrate that MMPs are critical effectors of invasion in the papillary and follicular thyroid cancer cell lines studied. Invasion is regulated by signaling through EGFR, an effect mediated by augmentation of gelatinase expression and activation. MMP inhibitors and growth factor antagonists may be effective tumoristatic agents for the treatment of aggressive thyroid carcinomas.
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Affiliation(s)
- Michael W Yeh
- Endocrine Surgery Laboratory, UCSF/Mt. Zion Medical Center, San Francisco, California 94115, USA.
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Zhong J, Gencay MMC, Bubendorf L, Burgess JK, Parson H, Robinson BWS, Tamm M, Black JL, Roth M. ERK1/2 and p38 MAP kinase control MMP-2, MT1-MMP, and TIMP action and affect cell migration: a comparison between mesothelioma and mesothelial cells. J Cell Physiol 2006; 207:540-52. [PMID: 16447244 DOI: 10.1002/jcp.20605] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Pleural malignant mesothelioma is a locally aggressive tumor of mesothelial cell origin. In other tumor types high expression of matrix metalloproteinase (MMP)-2, together with membrane-type1-MMP (MT1-MMP), and low levels of the tissue inhibitor of MMP (TIMP)-2 have been correlated with aggressive tumor progression and low survival rates. Therefore, we compared the expression and activation of these three factors and their regulation by two mesothelioma associated growth factors, platelet-derived growth factor (PDGF)-BB, and transforming growth factor (TGF)-beta1 in six human mesothelioma and one mesothelial cell line. Polymerase chain reaction (PCR), immunoblotting, zymography, and small inhibitory RNAs (siRNA) were used to study gene expression, protein activation, and signal transduction. To proof the relevance of our in vitro data immunohistochemistry was performed in tissue sections. PDGF-BB induced, while TGF-beta1 inhibited cell proliferation. PDGF-BB was a chemoattractant for mesothelial cells, and its effect was increased in the presence of TGF-beta1. TGF-beta1 stimulated the de novo synthesis of pro-MMP-2 in both cell types. Pro-MMP-2 synthesis involved p38 MAP kinase. In cell culture and tissue sections only mesothelial cells expressed MT1-MMP. Migration of mesothelioma cells was dependent on the presence of MT1-MMP. Migration, but not proliferation of mesothelioma cells was inhibited by oleoyl-N-hydroxylamide, TIMP-2, and siRNA for MT1-MMP. Our data suggest that in mesothelioma cells the phosphorylation of p38 MAP kinase is deregulated and is involved in pro-MMP-2 expression. Mesothelioma progression depends on an interaction with mesothelial cells that provide MT1-MMP necessary to activate pro-MMP-2 to facilitate migration through an extracellular matrix (ECM) layer.
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Affiliation(s)
- Jun Zhong
- Department of Pharmacology, The Woolcock Institute of Medical Research, University of Sydney, New South Wales, Australia
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Kroczynska B, Carbone M. Cross reactivity between many anti-human antibodies for their hamster homologs provide the tools to study the signal transduction pathway activated by asbestos and SV40 in the malignant mesothelioma model. Mol Carcinog 2006; 45:537-42. [PMID: 16649249 DOI: 10.1002/mc.20200] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The aim of this study was to test the possibility of using human antibodies to study the pathogenic mechanism of SV40 and asbestos in a hamster mesothelioma model. The cellular lysates from human and hamster primary mesothelial cells were tested by Western blot analysis. All of the antibodies we tested (HGF, Notch, VEGF, Sp1, p53, PP2A, p-ERK1, p-c-jun, Fra1, Fra2, MMP1, MMP9, NFkappaB p65, IkappaB, GAPDH) cross-reacted with their hamster counterparts. These data indicate that hamster mesothelioma model and more in general hamster experimental model, can be used for functional studies because many mouse, rabbit, and goat monoclonal antibodies prepared against human antigens cross-react with their hamster counterparts.
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Affiliation(s)
- Barbara Kroczynska
- Department of Pathology, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, Illinois 60153, USA
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Mukohara T, Civiello G, Davis IJ, Taffaro ML, Christensen J, Fisher DE, Johnson BE, Jänne PA. Inhibition of the met receptor in mesothelioma. Clin Cancer Res 2006; 11:8122-30. [PMID: 16299245 DOI: 10.1158/1078-0432.ccr-05-1191] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Expression of the Met receptor and its ligand, hepatocyte growth factor (HGF), has been observed in 74% to 100% and 40% to 85% of malignant pleural mesothelioma (MPM) specimens, respectively. HGF stimulation has been shown to enhance MPM cell proliferation, migration, cell scattering, and invasiveness. EXPERIMENTAL DESIGN To investigate a potential therapeutic role for the Met receptor in MPM, we examined the effects of PHA-665752, a specific small-molecule inhibitor of the Met receptor tyrosine kinase, in a panel of 10 MPM cell lines. RESULTS Two of the cell lines, H2461 and JMN-1B, exhibited autocrine HGF production as measured by ELISA (3.9 and 10.5 ng/mL, respectively, versus <0.05 ng/mL in other cell lines). Evaluation of PHA-665752 across the 10 MPM cell lines indicated that despite Met expression in all cell lines, only in cell lines that exhibited a Met/HGF autocrine loop, H2461 and JMN-1B, did PHA-665752 inhibit growth with an IC(50) of 1 and 2 micromol/L, respectively. No activating mutations in Met were detected in any of the cell lines. Consistent with observed growth inhibition, PHA-665752 caused cell cycle arrest at G(1)-S boundary accompanied by a dose-dependent decrease in phosphorylation of Met, p70S6K, Akt, and extracellular signal-regulated kinase 1/2. Growth of H2461 cells was also inhibited by neutralizing antibodies to HGF and by RNA interference knockdown of the Met receptor, confirming that growth inhibition observed was through a Met-dependent mechanism. PHA-665752 also reduced MPM in vitro cell migration and invasion. CONCLUSIONS Taken together, these findings suggest that inhibition of the Met receptor may be an effective therapeutic strategy for patients with MPM and provides a mechanism, the presence of a HGF/Met autocrine loop, by which to select patients for PHA-665752 treatment.
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Affiliation(s)
- Toru Mukohara
- Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
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Abstract
Malignant mesothelioma (MM) is an uncommon tumor with high mortality and morbidity rates. It arises from mesothelial cells that line the pleural, pericardial, peritoneal, and testicular cavities. This is a disease with an indolent course because tumors arise 20 to 40 years after exposure to an inciting agent. Extensive research has shown that mesothelial cells are transformed into MM cells through various chromosomal and cellular pathway defects. These changes alter the normal cells' ability to survive, proliferate, and metastasize. This article discusses the alterations that occur in transforming normal mesothelial cells into MM. It also details some of the signal transduction pathways that seem to be important in MM with the potential for novel targeted therapeutics.
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Affiliation(s)
- Evan Pisick
- Department of Medicine, Section of Hematology/Oncology, Tufts-New England Medical Center, Boston, MA, USA
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Davidson B, Risberg B, Berner A, Bedrossian CWM, Reich R. The biological differences between ovarian serous carcinoma and diffuse peritoneal malignant mesothelioma. Semin Diagn Pathol 2006; 23:35-43. [PMID: 17044194 DOI: 10.1053/j.semdp.2006.06.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Recent improvements in immunohistochemistry panels used for differentiating ovarian serous carcinoma/primary peritoneal carcinoma (OC/PPC) from diffuse malignant peritoneal mesothelioma (DMPM) have resulted in improved diagnostic rates for these tumors in both cytological and histological material. However, little is known about the biological characteristics that differentiate these two cancer types. We performed a comparative analysis of cancer-associated molecule expression data for a cohort consisting of up to 270 serous OC/PPC specimens (only peritoneal lesions) and 32 peritoneal MM. The molecules studied were nerve growth factor receptors (p75, p-TrkA), angiogenic factors (VEGF, IL-8, bFGF, heparanase), laminin receptors (the 67-kDa receptor and the alpha 6 integrin subunit), proteases (MMP-2), immune response mediators (HLA-G), and signaling molecules (the MAPK members ERK, JNK, and p38). The methods used were immunohistochemistry, Western blotting, and RT-PCR. DMPM specimens showed significantly higher expression of p75 (P < 0.001), p-TrkA (P < 0.001), and bFGF (P < 0.001), and significantly lower expression of the 67-kDa receptor (P < 0.001), alpha 6 integrin subunit (P = 0.025), VEGF (P < 0.001), IL-8 (P < 0.001), and HLA-G (P = 0.039) compared with OC/PPC. DMPM specimens showed higher activation ratio (phosphorylated/total enzyme ratio) of all three MAPK members (ERK, P = 0.017; JNK, P < 0.001; p38, P = 0.009) compared with OC/PPC. These data document significant differences in the expression of cancer- and metastasis-associated molecules in MM compared with ovarian carcinoma, and suggest that different biological pathways are involved in tumorigenesis and disease progression in these two tumors.
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Affiliation(s)
- Ben Davidson
- Department of Pathology, Norwegian Radium Hospital-National Hospital, University of Oslo, Oslo, Norway.
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Altomare DA, You H, Xiao GH, Ramos-Nino ME, Skele KL, De Rienzo A, Jhanwar SC, Mossman BT, Kane AB, Testa JR. Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth. Oncogene 2005; 24:6080-9. [PMID: 15897870 DOI: 10.1038/sj.onc.1208744] [Citation(s) in RCA: 127] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Malignant mesotheliomas (MMs) are very aggressive tumors that respond poorly to standard chemotherapeutic approaches. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been implicated in tumor aggressiveness, in part by mediating cell survival and reducing sensitivity to chemotherapy. Using antibodies recognizing the phosphorylated/activated form of AKT kinases, we observed elevated phospho-AKT staining in 17 of 26 (65%) human MM specimens. In addition, AKT phosphorylation was consistently observed in MMs arising in asbestos-treated mice and in MM cell xenografts. Consistent with reports implicating hepatocyte growth factor (HGF)/Met receptor signaling in MM, all 14 human and murine MM cell lines had HGF-inducible AKT activity. One of nine human MM cell lines had elevated AKT activity under serum-starvation conditions, which was associated with a homozygous deletion of PTEN, the first reported in MM. Treatment of this cell line with the mTOR inhibitor rapamycin resulted in growth arrest in G1 phase. Treatment of MM cells with the PI3K inhibitor LY294002 in combination with cisplatin had greater efficacy in inhibiting cell proliferation and inducing apoptosis than either agent alone. Collectively, these data indicate that MMs frequently express elevated AKT activity, which may be targeted pharmacologically to enhance chemotherapeutic efficacy. These findings also suggest that mouse models of MM may be useful for future preclinical studies of pharmaceuticals targeting the PI3K/AKT pathway.
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Affiliation(s)
- Deborah A Altomare
- Human Genetics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
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Li HW, Shan JX. Effects of hepatocyte growth factor/scatter factor on the invasion of colorectal cancer cells in vitro. World J Gastroenterol 2005; 11:3877-81. [PMID: 15991286 PMCID: PMC4504889 DOI: 10.3748/wjg.v11.i25.3877] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Hepatocyte growth factor (HGF) is a multifunctional growth factor which has pleiotrophic biological effects on epithelial cells, such as proliferation, motogenesis, invas-iveness and morphogenesis. There are few reports about the role of HGF played in the colorectal cancer invasion. In the present study, we tried to investigate the possible mechanism of HGF involved in the invasion of colorectal cancer cells in vitro.
METHODS: Matrigel migration assay was used to analyze the migrational ability of Caco-2 and Colo320 in vitro. We detected the mRNA expressive levels of MMP-2, MMP-9 and their natural inhibitors TIMP-1, TIMP-2 in Caco-2 cells by reverse-transcription polymerase chain reaction (PCR) technique.
RESULTS: After 48 h incubation, there were notable differences when we compared the migrational numbers of Caco-2 cells in the group of HGF and PD98059 (the inhibitor of p42/p44MAPK) with the control (104.40 ± 4.77 vs 126.80 ± 5.40, t = 7.17, P = 0.002 < 0.01; 104.40 ± 4.77 vs 82.80 ± 4.15, t = 7.96, P = 0.001 < 0.01). The deviation between the HGF and PD98059 was significant (P < 0.01). Compared with controls, MMP-2 and MMP-9 mRNA expres-sions were up-regulated by HGF (0.997 ± 0.011 vs 1.207 ± 0.003, t = 35.002,P = 0.001 < 0.01; 0.387 ± 0.128 vs 0.971 ± 0.147, t = 106.036, P = 0.0000 < 0.01, respectively); compared with controls, TIMP-1, TIMP-2 mRNA expressions were increased by PD98059 (1.344 ± 0.007 vs 1.905 ± 0.049, t = 17.541, P = 0.003 < 0.01; 1.286 ± 0.020 vs 1.887 ± 0.022, t = 24.623, P = 0.002 < 0.01, respectively).
CONCLUSION: HGF promoted Caco-2 migration mainly by p42/p44MAPK pathway; HGF/SF stimulated the expression of MMP-2, MMP-9 in Caco-2 and enabled tumoral cells to damage the ECM and reach the distant organ and develop metastasis; HGF played the function of promoted-invasion and promoted-metastasis, in which cellular selection was possible.
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Affiliation(s)
- Hong-Wu Li
- Department of Oncology, First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, China.
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Stella MC, Trusolino L, Pennacchietti S, Comoglio PM. Negative feedback regulation of Met-dependent invasive growth by Notch. Mol Cell Biol 2005; 25:3982-96. [PMID: 15870272 PMCID: PMC1087707 DOI: 10.1128/mcb.25.10.3982-3996.2005] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The hepatocyte growth factor (HGF) receptor encoded by the Met oncogene controls a genetic program-known as "invasive growth"-responsible for several developmental processes and involved in cancer invasion and metastasis. This program functions through several regulatory gene products, as yet largely unknown, both upstream and downstream of Met. Here we show that activation of the Notch receptor results in transcriptional down-regulation of Met, suppression of HGF-dependent Ras signaling, and impairment of HGF-dependent cellular responses. In turn, Met activation leads to transcriptional induction of the Notch ligand Delta and the Notch effector HES-1, indicating that Met is able to self-tune its own protein levels and the ensuing biochemical and biological outputs through stimulation of the Notch pathway. By using branching morphogenesis of the tracheal system in Drosophila as a readout of invasive growth, we also show that exogenous expression of a constitutively active form of human Met induces enhanced sprouting of the tracheal tree, a phenotype that is further increased in embryos lacking Notch function. These results unravel an in-built mechanism of negative feedback regulation in which Met activation leads to transcriptional induction of Notch function, which in turn limits HGF activity through repression of the Met oncogene.
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Affiliation(s)
- M Cristina Stella
- Institute for Cancer Research and Treatment, University of Turin School of Medicine, Division of Molecular Oncology, IV Floor, Str. Prov. 142, Km. 3,95, 10060 Candiolo, Torino, Italy.
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Abstract
Malignant pleural mesothelioma (MPM) is a seemingly uncommon tumor whose incidence has in fact increased steadily and progressively over the last 30 years. Indeed, an actual "epidemic" is expected in Europe over the next 20 years. Despite unquestionable improvement in the diagnostic methods at our disposal and the availability of new treatment strategies, the prognosis of MPM patients remains dramatically poor (12 to 18 months' median survival from diagnosis), although exceptional cases of long-survivors are reported in all literature series. The current review will cover the dramatic improvements in the treatment of this rare disease that have been recently achieved, as well as the promise that new, molecular-targeted therapies, such as bortezomid, mTOR ( m ammalian t arget o f r apamycin) inhibitors, and Met inhibitors, seem to offer for the next few years. With pemetrexed we now have a drug that is able to impact patient survival. Together with the newer drugs, rapidly emerging from the laboratory to be applied in the clinic, we have the hope of making further advances in the struggle against this disease.
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Lumb PD, Suvarna SK. Metastasis in pleural mesothelioma. Immunohistochemical markers for disseminated disease. Histopathology 2004; 44:345-52. [PMID: 15049900 DOI: 10.1111/j.1365-2559.2004.01844.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
AIMS To examine 13 cases of mesothelioma with metastases and compare these with 29 biopsy samples of patients without metastases. Metastatic disease was defined as tumour in which tumour appeared in a different cavity/tissue of the body and which showed no direct spread. Consequently, mediastinal nodal and parenchymal lung spread was excluded. METHODS AND RESULTS Standard sections were prepared and stained according to the manufacturers' protocols. The antibodies used were MIB-1, nm23, Bcl-2, MMP-9, EMMPRIN (CD147) and alpha-catenin. Scoring employed a grading system (0/1/2/3), and was performed by two pathologists independently. The tissues revealed no significant staining differences for MIB-1, Bcl-2, MMP-9 or EMMPRIN, and therefore no linkage to metastatic potential was determined. Alpha-Catenin showed a diminished level of expression in cases of metastatic mesothelioma (P = 0.024), possibly reflecting dimished catenin-cadherin binding and paralleling data from other tumours. nm23 showed greater staining in metastatic tumours when compared with the controls (P = 0.001). Intriguingly, the nm23 staining pattern was the reverse of that expected. This reversed pattern has been noted before in other tumours and therefore a biological prognostic event may exist for this antibody test and mesothelioma metastasis. CONCLUSION There may be a place for nm23 and possibly alpha-catenin in immunohistochemical assessment of mesothelioma metastatic potential. However, MIB-1, Bcl-2, MMP-9 and EMMPRIN (CD147) do not show significant staining results.
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Affiliation(s)
- P D Lumb
- Department of Forensic Pathology, University of Sheffield, The Northern General Hospital, Sheffield, UK
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Shinomiya N, Gao CF, Xie Q, Gustafson M, Waters DJ, Zhang YW, Vande Woude GF. RNA interference reveals that ligand-independent met activity is required for tumor cell signaling and survival. Cancer Res 2004; 64:7962-70. [PMID: 15520203 DOI: 10.1158/0008-5472.can-04-1043] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Hepatocyte growth factor/scatter factor-Met signaling has been implicated in tumor growth, invasion, and metastasis. Suppression of this signaling pathway by targeting the Met protein tyrosine kinase may be an ideal strategy for suppressing malignant tumor growth. Using RNA interference technology and adenovirus vectors carrying small-interfering RNA constructs (Ad Met small-interfering RNA) directed against mouse, canine, and human Met, we can knock down c-met mRNA. We show a dramatic dependence on Met in both ligand-dependent and ligand-independent mouse, canine, and human tumor cell lines. Mouse mammary tumor (DA3) cells and Met-transformed NIH3T3 (M114) cells, as well as both human and canine prostate cancer (PC-3 and TR6LM, human sarcoma (SK-LMS-1), glioblastoma (DBTRG), and gastric cancer (MKN45) cells, all display a dramatic reduction of Met expression after infection with Ad Met small-interfering RNA. In these cells, we observe suppression of tumor cell growth and viability in vitro as well as inhibition of hepatocyte growth factor/scatter factor-mediated scattering and invasion in vitro, whether Met activation was ligand dependent or not. Importantly, Ad Met small-interfering RNA led to apoptotic cell death in many of the tumor cell lines, especially DA3 and MKN45, but did not adversely affect MDCK canine kidney cells. Met small-interfering RNA also abrogated downstream Met signaling to molecules such as Akt and p44/42 mitogen-activated protein kinase. We further show that intratumoral infection with c-met small-interfering RNA adenovirus results in a substantial reduction in tumor growth. Thus, Met small-interfering RNA adenoviruses are reliable tools for studying Met function and raise the possibility of their application for cancer therapy.
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Affiliation(s)
- Nariyoshi Shinomiya
- Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
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Vande Broek I, Asosingh K, Allegaert V, Leleu X, Facon T, Vanderkerken K, Van Camp B, Van Riet I. Bone marrow endothelial cells increase the invasiveness of human multiple myeloma cells through upregulation of MMP-9: evidence for a role of hepatocyte growth factor. Leukemia 2004; 18:976-82. [PMID: 14999296 DOI: 10.1038/sj.leu.2403331] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The migration of multiple myeloma (MM) cells from the circulation into the bone marrow (BM) implicates that they must have the capacity to cross the BM endothelium including the subendothelial basement membrane. In this study, human CD138+ MM cells were immunomagnetically isolated from BM samples of MM patients and their invasion through Matrigel, that is, a reconstituted basement membrane, was determined. We demonstrated that primary MM cells have the capacity to transmigrate through basement membrane and that this invasiveness was considerably increased when assessed on Matrigel filters coated with BM endothelial cells (EC) (4LHBMEC line) (transendothelial invasion). The isolated MM cells were shown by zymography to secrete matrix metalloproteinase (MMP)-9 and anti-MMP-9 antibodies inhibited transendothelial invasion, indicating that MMP-9 is involved in this process. BM EC were found to increase the MMP-9 secretion in MM cells, indicating that EC enhance MM cell invasion through stimulation of MMP-9 secretion. BM EC were found to produce hepatocyte growth factor (HGF), and this cytokine also stimulated MMP-9 secretion in MM cells, while anti-HGF antibodies significantly inhibited EC-stimulated MM cell invasion. In summary, our findings provide evidence that MM cell-BM EC interactions enhance the invasion of human MM cells through stimulation of MMP-9 secretion.
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Affiliation(s)
- I Vande Broek
- Department of Hematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium
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Watelet JB, Bachert C, Claeys C, Van Cauwenberge P. Matrix metalloproteinases MMP-7, MMP-9 and their tissue inhibitor TIMP-1: expression in chronic sinusitis vs nasal polyposis. Allergy 2004; 59:54-60. [PMID: 14674934 DOI: 10.1046/j.1398-9995.2003.00364.x] [Citation(s) in RCA: 146] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Nasal polyps (NP) are characterized by pseudocyst formation, whereas the mucosa in chronic sinusitis (CS) only shows a limited oedema. Matrix metalloproteinases (MMPs) are a family of endopeptidases able to degrade the extracellular matrix. Differences in histological features between CS and NP might be related to the respective expression of MMPs and their tissue inhibitors (TIMPs). OBJECTIVE The aim of this study was to investigate MMP-7, MMP-9 and TIMP-1 proteins in NP and CS in comparison with normal mucosa. METHODS Nasal samples, obtained from controls (n = 10), from NP (n = 8) and from CS (n = 10), were analysed by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). RESULTS In NP, compared with controls, staining for MMP-9 and MMP-7 appeared in blood vessels. Matrix metalloproteinase-9-positive inflammatory cells could be detected in increased numbers in pseudocyst formations. Concentrations of MMP-9 protein was found significantly increased in both CS and NP compared with controls, while MMP-7 was significantly increased in NP compared with controls and CS. Tissue inhibitors of metalloproteinase-1 protein was significantly increased in CS and NP when compared with controls. CONCLUSIONS Chronic sinusitis and NP show different pattern of MMP-7/-9 and TIMP-1 expression. We suggest that this difference in regulation of enzymes is related to the respective tissue remodelling observed in both diseases.
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Affiliation(s)
- J B Watelet
- Department of Otorhinolaryngology, University Hospital Ghent, Ghent, Belgium
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Abstract
Malignant pleural mesothelioma is an aggressive malignancy with no known single curative modality. Most patients are candidates for chemotherapy at some point in their treatment, but no standard regimen has been established. Several phase II single-agent and combination chemotherapy studies have been performed over the past 2 decades. Although the true impact of chemotherapy in mesothelioma remains to be determined, agents with consistent antitumor activity include doxorubicin, platinum agents, and antimetabolites. Combination chemotherapy is associated with higher response rates, but not necessarily longer median survivals. Large randomized trials, which are currently ongoing or have been performed in the past few years, will yield important answers in regard to the role of chemotherapy and the efficacy of various single and combination chemotherapy agents. Furthermore, the biologic and genetic studies of mesothelioma have identified several receptor tyrosine kinases that are aberrantly expressed in these tumors. Orally available small molecule inhibitors of several receptor tyrosine kinases have been developed and are now being evaluated in clinical trials.
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Affiliation(s)
- Pasi A Janne
- Lowe Center for Thoracic Oncology and Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
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Abstract
OBJECTIVE To understand the mechanism of pathologic capillary leak in the critically ill patient. DESIGN Review of normal and altered physiology of the microvasculature. Review of recent literature describing pathogenesis, mediators, and interventions influencing capillary leak and microvascular repair. SETTING In vitro and in vivo studies, the latter including animal and human subjects. MEASUREMENTS AND MAIN RESULTS Capillary leak with resultant edema develops in the critical care setting on the basis of perturbations in Starling's equation, primarily as a result of increased capillary permeability to larger molecules. This process is most likely fueled by inflammatory mediators or mechanical stress. Attempts to prevent or treat this process remain largely unsuccessful; resuscitation is more often symptomatic than therapeutic. Models of microvascular repair focus on discrete injury and may not be applicable to the recovery of capillary damage secondary to a systemic leak CONCLUSIONS Our understanding of capillary leak syndrome remains fragmented and weighted toward specific mediators contributing to the leak. The implications of extensive edema and the mechanism by which it resolves continue to be the subject of speculation rather than study.
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Affiliation(s)
- Rhonda S Fishel
- Department of Surgery, Sinai Hospital of Baltimore, MD 21215, USA
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Edwards JG, McLaren J, Jones JL, Waller DA, O'Byrne KJ. Matrix metalloproteinases 2 and 9 (gelatinases A and B) expression in malignant mesothelioma and benign pleura. Br J Cancer 2003; 88:1553-9. [PMID: 12771921 PMCID: PMC2377107 DOI: 10.1038/sj.bjc.6600920] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Matrix metalloproteinases (MMPs), in particular the gelatinases (MMP-2 and -9), play a significant role in tumour invasion and angiogenesis. The expression and activities of MMPs have not been characterised in malignant mesothelioma (MM) tumour samples. In a prospective study, gelatinase activity was evaluated in homogenised supernatants of snap frozen MM (n=35), inflamed pleura (IP, n=12) and uninflammed pleura (UP, n=14) tissue specimens by semiquantitative gelatin zymography. Matrix metalloproteinases were correlated with clinicopathological factors and with survival using Kaplan-Meier and Cox proportional hazard models. In MM, pro- and active MMP-2 levels were significantly greater than for MMP-9 (P=0.006, P<0.001). Active MMP-2 was significantly greater in MM than in UP (P=0.04). MMP-2 activity was equivalent between IP and MM, but both pro- and active MMP-9 activities were greater in IP (P=0.02, P=0.009). While there were trends towards poor survival with increasing total and pro-MMP-2 activity (P=0.08) in univariate analysis, they were both independent poor prognostic factors in multivariate analysis in conjunction with weight loss (pro-MMP-2 P=0.03, total MMP-2 P=0.04). Total and pro-MMP-2 also contributed to the Cancer and Leukemia Group B prognostic groups. MMP-9 activities were not prognostic. Matrix metalloproteinases, and in particular MMP-2, the most abundant gelatinase, may play an important role in MM tumour growth and metastasis. Agents that reduce MMP synthesis and/or activity may have a role to play in the management of MM.
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Affiliation(s)
- J G Edwards
- University Department of Medical Oncology, Osborne Building, Leicester Royal Infirmary, Leicester LE1 5WW, UK
- Department of Respiratory Medicine and Thoracic Surgery, Glenfield Hospital NHS Trust, Groby Road, Leicester LE3 9QP, UK
| | - J McLaren
- Department of Obstetrics and Gynaecology, University of Leicester, Robert Kilpatrick Building, Leicester Royal Infirmary, Leicester LE1 5WW, UK
| | - J L Jones
- Department of Pathology, University of Leicester, Robert Kilpatrick Building, Leicester Royal Infirmary, Leicester LE1 5WW, UK
| | - D A Waller
- Department of Respiratory Medicine and Thoracic Surgery, Glenfield Hospital NHS Trust, Groby Road, Leicester LE3 9QP, UK
| | - K J O'Byrne
- University Department of Medical Oncology, Osborne Building, Leicester Royal Infirmary, Leicester LE1 5WW, UK
- University Department of Medical Oncology, Osborne Building, Leicester Royal Infirmary, Leicester LE1 5WW, UK. E-mail:
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Liu Z, Klominek J. Regulation of matrix metalloprotease activity in malignant mesothelioma cell lines by growth factors. Thorax 2003; 58:198-203. [PMID: 12612292 PMCID: PMC1746590 DOI: 10.1136/thorax.58.3.198] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BACKGROUND The extracellular matrix metalloproteases (MMPs) produced by tumour and stromal cells are believed to play a key role in tumour cell invasion and metastasis. Malignant mesothelioma is a highly aggressive tumour. Previous studies have shown that malignant mesothelioma cells express MMP-1, -2, -3, -7 and -9. However, the regulation of MMP expression in malignant mesothelioma cells has not been thoroughly investigated. METHODS The effects of a number of growth factors on the secretion of MMP-2, -3 and -9 in malignant mesothelioma cells were studied by substrate zymography. The expression of relevant growth factor receptors in malignant mesothelioma cells was also examined using RT-PCR. RESULTS The exposure of malignant mesothelioma cells to different growth factors including epidermal growth factor (EGF), transforming growth factor-alpha, amphiregulin, heparin binding EGF, beta-cellulin (BTC), stem cell factor, insulin-like growth factors I and II, acidic and basic fibroblast growth factors, and hepatocyte growth factor increased secretion of MMP-9 and/or MMP-3. EGF receptor ligands BTC and EGF had the most potent effect on MMP-9 and MMP-3 production, respectively. Production of MMP-2 was not affected by any growth factors used in this study. We have also demonstrated mRNA expression of different growth factor receptors in malignant mesothelioma cells, and found that the tyrosine kinase inhibitor genistein inhibited the increased production of MMPs resulting from stimulation with different growth factors. CONCLUSION This study shows, for the first time, the broad extent of regulation of MMPs by various growth factors in malignant mesothelioma cells.
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Affiliation(s)
- Z Liu
- Division of Clinical Immunology and Division of Respiratory Medicine and Allergology, Karolinska Institute at Huddinge University Hospital, S-141 86 Stockholm, Sweden
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Kort EJ, Jones A, Daumbach M, Hudson EA, Buckner B, Resau JH. Quantifying cell scattering: the blob algorithm revisited. Cytometry A 2003; 51:119-26. [PMID: 12541286 DOI: 10.1002/cyto.a.10010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND A method to objectively quantify cell scattering would permit quantitative evaluation of therapies and compounds intended to affect this physiologic process, which has relevance to normal (e.g., development) and pathologic (e.g., metastasis) events. METHODS A grid-based modified blob analysis was performed on a set of images of Madin-Darby Canine Kidney (MDCK) cells to quantify the following parameters: the number of cellular clusters in each image, the size of the clusters in terms of pixel counts, and the number of cells in each cluster. These parameters were used as measures of cell scattering and were compared with subjective assessments of scattering made by three experienced examiners. RESULTS The quantitative parameters correlated strongly to subjective assessments. The algorithm displayed a different concept of "clustering" than the examiners and consistently identified more clusters than did the examiners. There was close agreement in the number of cells counted. All three quantitative parameters correlated strongly to the subjective scattering scores, as follows: cluster count (r(s) = -0.765 to -0.789, P < 0.0001), cluster size in pixels (r(s) = 0.838 to 0.845, P < 0.0001), and cluster size in cells (r(s) = 0.758 to 0.804, P < 0.0001). The parameters were continuous, providing greater resolving power than ordinal subjective scores. CONCLUSIONS The findings confirmed that our algorithm reproduces the traditional classification of scattering with improved resolution, quantification, and objectivity.
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Affiliation(s)
- Eric J Kort
- Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
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To Y, Dohi M, Matsumoto K, Tanaka R, Sato A, Nakagome K, Nakamura T, Yamamoto K. A two-way interaction between hepatocyte growth factor and interleukin-6 in tissue invasion of lung cancer cell line. Am J Respir Cell Mol Biol 2002; 27:220-6. [PMID: 12151314 DOI: 10.1165/ajrcmb.27.2.4804] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Although both hepatocyte growth factor (HGF) and interleukin (IL)-6 play important roles in invasion of cancer cells, interaction between these two critical factors has not been well elucidated. In the present study we demonstrated a two-way interaction between HGF and IL-6 in in vitro invasion of a lung cancer cell line. A549 lung adenocarcinoma cells were stimulated with IL-6, and this treatment induced an upregulation of c-Met/HGF receptor mRNA expression in the cells. In addition, IL-6 enhanced the HGF-induced in vitro cell invasion. This effect was abolished by pretreatment of the cells with either anti-IL-6 neutralizing antibody or with anti-c-Met/HGF receptor blocking antibody. We also found that HGF upregulated the expression of IL-6 receptor mRNA in the same cell line, and that this upregulation enhanced the IL-6-induced cell invasion. Finally, costimulation with HGF and IL-6 showed an additive effect on invasion, and this effect was mediated by production of matrix metalloproteinase (MMP)-2 and MMP-9. These results suggest that HGF and IL-6 upregulate each other's receptors, and thus would cooperatively enhance tissue invasion. They also suggest an "autocrine circuit" among cytokines and growth factors in certain cancer cells which functions to accelerate their biologic activities such as metastatic property.
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Affiliation(s)
- Yasuo To
- Pulmonary Section, Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
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