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Reddy RA, Varshini MS, Kumar RS. Matrix Metalloproteinase-2 (MMP-2): As an Essential Factor in Cancer Progression. Recent Pat Anticancer Drug Discov 2025; 20:26-44. [PMID: 37861020 PMCID: PMC11826896 DOI: 10.2174/0115748928251754230922095544] [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: 03/03/2023] [Revised: 07/21/2023] [Accepted: 08/24/2023] [Indexed: 10/21/2023]
Abstract
The development of cancer has been a multistep process involving mutation, proliferation, survival, invasion, and metastasis. Of all the characteristics of cancer, metastasis is believed to be the hallmark as it is responsible for the highest number of cancer-related deaths. In connection with this, Matrix metalloproteinases (MMPs), that has a role in metastasis, are one of the novel therapeutic targets. MMPs belong to the family of zinc-dependent endopeptidases and are capable of degrading the components of the extracellular matrix (ECM). The role of MMPs in ECM remodeling includes tissue morphogenesis, uterine cycling, growth, tissue repair, and angiogenesis. During pathological conditions, MMPs play a critical role in the excessive degradation of ECM which includes arthritis, tumour invasion, tumour metastasis, and several other autoimmune disorders. Moreover, they are believed to be involved in many physiological aspects of the cell, such as proliferation, migration, differentiation, angiogenesis, and apoptosis. It is reported that dysregulation of MMP in a variety of cancer subtypes have a dual role in tumour growth and metastasis processes. Further, multiple studies suggest the therapeutic potential of targeting MMP in invading cancer. The expression of MMP-2 correlates with the clinical characteristics of cancer patients, and its expression profile is a new diagnostic and prognostic biomarker for a variety of human diseases. Hence, manipulating the expression or function of MMP-2 may be a potential treatment strategy for different diseases, including cancers. Hence, the present review discusses the therapeutic potential of targeting MMP in various types of cancers and their recent patents.
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Vieira GDS, Kimura TDC, Scarini JF, de Lima-Souza RA, Lavareze L, Emerick C, Gonçalves MT, Damas II, Figueiredo-Maciel T, Sales de Sá R, Aquino IG, Gonçalves de Paiva JP, Fernandes PM, Gonçalves MWA, Kowalski LP, Altemani A, Fillmore GC, Mariano FV, Egal ESA. Hematopoietic colony-stimulating factors in head and neck cancers: Recent advances and therapeutic challenges. Cytokine 2024; 173:156417. [PMID: 37944421 DOI: 10.1016/j.cyto.2023.156417] [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: 10/08/2023] [Accepted: 10/31/2023] [Indexed: 11/12/2023]
Abstract
Colony-stimulating factors (CSFs) are key cytokines responsible for the production, maturation, and mobilization of the granulocytic and macrophage lineages from the bone marrow, which have been gaining attention for playing pro- and/or anti-tumorigenic roles in cancer. Head and neck cancers (HNCs) represent a group of heterogeneous neoplasms with high morbidity and mortality worldwide. Treatment for HNCs is still limited even with the advancements in cancer immunotherapy. Novel treatments for patients with recurrent and metastatic HNCs are urgently needed. This article provides an in-depth review of the role of hematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and interleukin-3 (IL-3; also known as multi-CSF) in the HNCs tumor microenvironment. We have reviewed current results from clinical trials using CSFs as adjuvant therapy to treat HNCs patients, and also clinical findings reported to date on the therapeutic application of CSFs toxicities arising from chemoradiotherapy.
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Affiliation(s)
- Gustavo de Souza Vieira
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil; Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Talita de Carvalho Kimura
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil; Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - João Figueira Scarini
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil; Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Reydson Alcides de Lima-Souza
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil; Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Luccas Lavareze
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil; Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Carolina Emerick
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil; Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Mayara Trevizol Gonçalves
- Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Ingrid Iara Damas
- Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Tayná Figueiredo-Maciel
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil; Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Raisa Sales de Sá
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil
| | - Iara Gonçalves Aquino
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil
| | - João Paulo Gonçalves de Paiva
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil
| | - Patrícia Maria Fernandes
- Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Moisés Willian Aparecido Gonçalves
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil; Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Luiz Paulo Kowalski
- Department of Head and Neck Surgery, School of Medicine, University of São Paulo (USP), São Paulo, Brazil; Department of Head and Neck Surgery and Otolaryngology, AC Camargo Cancer Center, São Paulo, Brazil
| | - Albina Altemani
- Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Gary Chris Fillmore
- Biorepository and Molecular Pathology, Huntsman Cancer Institute, University of Utah (UU), Salt Lake City, UT, United States
| | - Fernanda Viviane Mariano
- Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
| | - Erika Said Abu Egal
- Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil; Biorepository and Molecular Pathology, Huntsman Cancer Institute, University of Utah (UU), Salt Lake City, UT, United States.
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Kostecki KL, Iida M, Wiley AL, Kimani S, Mehall B, Tetreault K, Alexandridis R, Yu M, Hong S, Salgia R, Bruce JY, Birge RB, Harari P, Wheeler DL. Dual Axl/MerTK inhibitor INCB081776 creates a proinflammatory tumor immune microenvironment and enhances anti-PDL1 efficacy in head and neck cancer. Head Neck 2023; 45:1255-1271. [PMID: 36939040 PMCID: PMC10079616 DOI: 10.1002/hed.27340] [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: 10/31/2022] [Revised: 02/01/2023] [Accepted: 02/22/2023] [Indexed: 03/21/2023] Open
Abstract
BACKGROUND The tyrosine kinase receptors Axl and MerTK are highly overexpressed in head and neck cancer (HNC) cells, where they are critical drivers of survival, proliferation, metastasis, and therapeutic resistance. METHODS We investigated the role of Axl and MerTK in creating an immunologically "cold" tumor immune microenvironment (TIME) by targeting both receptors simultaneously with a small molecule inhibitor of Axl and MerTK (INCB081776). Effects of INCB081776 and/or anti-PDL1 on mouse oral cancer (MOC) cell growth and on the TIME were evaluated. RESULTS Targeting Axl and MerTK can reduce M2 and induce M1 macrophage polarization. In vivo, INCB081776 treatment alone or with anti-PDL1 appears to slow MOC tumor growth, increase proinflammatory immune infiltration, and decrease anti-inflammatory immune infiltration. CONCLUSIONS This data indicates that simultaneous targeting of Axl and MerTK with INCB081776, either alone or in combination with anti-PDL1, slows tumor growth and creates a proinflammatory TIME in mouse models of HNC.
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Affiliation(s)
- Kourtney L Kostecki
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Mari Iida
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Anne L Wiley
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Stanley Kimani
- Rutgers Biomedical Health and Sciences, Rutgers University, Newark, NJ, USA
| | - Bridget Mehall
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Kaitlin Tetreault
- Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Roxana Alexandridis
- Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Menggang Yu
- Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Seungpyo Hong
- Pharmaceutical Sciences Division, University of Wisconsin School of Pharmacy, Madison, WI, USA
- Yonsei Frontier Lab and Department of Pharmacy, Yonsei University, Seoul, Korea
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | - Ravi Salgia
- Department of Medical Oncology and Experimental Therapeutics, Comprehensive Cancer Center, City of Hope, Duarte, CA, USA
| | - Justine Y Bruce
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Raymond B Birge
- Rutgers Biomedical Health and Sciences, Rutgers University, Newark, NJ, USA
| | - Paul Harari
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | - Deric L Wheeler
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
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Lopes-Santos G, Tjioe KC, Magalhaes MADO, Oliveira DT. The role of granulocyte-macrophage colony-stimulating factor in head and neck cancer. Arch Oral Biol 2023; 147:105641. [PMID: 36753900 DOI: 10.1016/j.archoralbio.2023.105641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/20/2023] [Accepted: 02/02/2023] [Indexed: 02/05/2023]
Abstract
OBJECTIVE To review the molecular mechanisms and biological roles of granulocyte-macrophage colony-stimulating factor (GM-CSF) in head and neck squamous cell carcinoma, highlighting its potential clinical applications. DESIGN The search terms "granulocyte-macrophage colony-stimulating factor", "GM-CSF", "CSF2″ and "head and neck squamous cell carcinoma" or "head and neck cancer" were queried in the PubMed/MEDLINE and Scopus databases. RESULTS Despite of being a widely expressed cytokine, the number of studies investigating the specific roles of GM-CSF in head and neck cancer was limited. Most of them investigated GM-CSF in conjunction with other cytokines. When studied alone, conflicting findings were observed in head and neck squamous cell carcinoma. GM-CSF has been shown to induce angiogenesis and local tumor invasion. Additionally, it has also been implicated in immune evasion. On the other hand, GM-CSF stimulated the differentiation of dendritic cells, which are responsible for presenting tumor antigens, and for the regulation of T cell function. Even with these paradoxical effects, there are few studies investigating the potential of GM-CSF as adjuvant therapy in head and neck cancer. CONCLUSION The effects of GM-CSF in head and neck cancer may be pro- or antitumor. Understanding how one arm and not the other is activated is essential to assess the applicability and the safety of this cytokine as a therapeutic agent.
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Affiliation(s)
- Gabriela Lopes-Santos
- Department of Surgery, Stomatology, Pathology, and Radiology, Area of Pathology, Bauru School of Dentistry, University of São Paulo, Alameda Octávio Pinheiro Brisolla, 9-75, Bauru, São Paulo 17012-901, Brazil.
| | - Kellen Cristine Tjioe
- Georgia Cancer Center, Augusta University, 1410 Laney Walker Blvd., CN2236B, Augusta, GA 30912, USA.
| | | | - Denise Tostes Oliveira
- Department of Surgery, Stomatology, Pathology, and Radiology, Area of Pathology, Bauru School of Dentistry, University of São Paulo, Alameda Octávio Pinheiro Brisolla, 9-75, Bauru, São Paulo 17012-901, Brazil.
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Vuttaradhi VK, Ezhil I, Ramani D, Kanumuri R, Raghavan S, Balasubramanian V, Saravanan R, Kanakarajan A, Joseph LD, Pitani RS, Sundaram S, Sjolander A, Venkatraman G, Rayala SK. Inflammation-induced PELP1 expression promotes tumorigenesis by activating GM-CSF paracrine secretion in the tumor microenvironment. J Biol Chem 2022; 298:101406. [PMID: 34774800 PMCID: PMC8671644 DOI: 10.1016/j.jbc.2021.101406] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 10/13/2021] [Accepted: 11/09/2021] [Indexed: 01/15/2023] Open
Abstract
The inflammatory tumor microenvironment has been implicated as a major player fueling tumor progression and an enabling characteristic of cancer, proline, glutamic acid, and leucine-rich protein 1 (PELP1) is a novel nuclear receptor coregulator that signals across diverse signaling networks, and its expression is altered in several cancers. However, investigations to find the role of PELP1 in inflammation-driven oncogenesis are limited. Molecular studies here, utilizing macrophage cell lines and animal models upon stimulation with lipopolysaccharide (LPS) or necrotic cells, showed that PELP1 is an inflammation-inducible gene. Studies on the PELP1 promoter and its mutant identified potential binding of c-Rel, an NF-κB transcription factor subunit, to PELP1 promoter upon LPS stimulation in macrophages. Recruitment of c-Rel onto the PELP1 promoter was validated by chromatin immunoprecipitation, further confirming LPS mediated PELP1 expression through c-Rel-specific transcriptional regulation. Macrophages that overexpress PELP1 induces granulocyte-macrophage colony-stimulating factor secretion, which mediates cancer progression in a paracrine manner. Results from preclinical studies with normal-inflammatory-tumor progression models demonstrated a progressive increase in the PELP1 expression, supporting this link between inflammation and cancer. In addition, animal studies demonstrated the connection of PELP1 in inflammation-directed cancer progression. Taken together, our findings provide the first report on c-Rel-specific transcriptional regulation of PELP1 in inflammation and possible granulocyte-macrophage colony-stimulating factor-mediated transformation potential of activated macrophages on epithelial cells in the inflammatory tumor microenvironment, reiterating the link between PELP1 and inflammation-induced oncogenesis. Understanding the regulatory mechanisms of PELP1 may help in designing better therapeutics to cure various inflammation-associated malignancies.
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Affiliation(s)
- Veena Kumari Vuttaradhi
- Molecular Oncology Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
| | - Inemai Ezhil
- Molecular Oncology Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
| | - Divya Ramani
- Molecular Oncology Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India; Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Rahul Kanumuri
- Molecular Oncology Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India; Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Swetha Raghavan
- Molecular Oncology Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
| | - Vaishnavi Balasubramanian
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Roshni Saravanan
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Archana Kanakarajan
- Department of Pathology, Sri Ramachandra Medical College, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Leena Dennis Joseph
- Department of Pathology, Sri Ramachandra Medical College, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Ravi Shankar Pitani
- Department of Community Medicine, Sri Ramachandra Medical College, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Sandhya Sundaram
- Department of Pathology, Sri Ramachandra Medical College, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Anita Sjolander
- Cell Pathology, Department of Translational Medicine, Clinical Research Centre, Skåne University Hospital, Lund University, Malmö, Sweden
| | - Ganesh Venkatraman
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India.
| | - Suresh Kumar Rayala
- Molecular Oncology Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India.
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Kitamura N, Sento S, Sasabe E, Kiyasu K, Nakaji K, Daibata M, Yamamoto T. Vertebral fracture and splenomegaly in a head and neck cancer producing granulocyte colony-stimulating factor: A case report of systemic complications associated with a cytokine-producing solid tumor. Mol Clin Oncol 2021; 15:202. [PMID: 34462658 PMCID: PMC8375029 DOI: 10.3892/mco.2021.2364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 06/15/2021] [Indexed: 12/01/2022] Open
Abstract
Granulocyte colony-stimulating factor (G-CSF)-producing tumors are rare and are associated with a poor prognosis when they occur in the lungs and the head and neck region. Positron emission tomography/computed tomography has been reported to show systemic specific accumulation of fluorodeoxyglucose in these cases, but the systemic complications associated with the cytokines produced are not well known. We herein present the case of a G-CSF-producing maxillary sinus squamous cell carcinoma in a 73-year-old Japanese woman with a vertebral fracture and splenomegaly. These findings are known severe adverse events of high-dose recombinant human G-CSF treatment. The aim of the present study was to further discuss the hypothesis that cytokines produced by solid tumors may induce spinal vertebral fracture and splenomegaly.
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Affiliation(s)
- Naoya Kitamura
- Department of Oral and Maxillofacial Surgery, Kochi Medical School, Kochi University, Kochi 783-8505, Japan
| | - Shinya Sento
- Department of Oral and Maxillofacial Surgery, Kochi Medical School, Kochi University, Kochi 783-8505, Japan
| | - Eri Sasabe
- Department of Oral and Maxillofacial Surgery, Kochi Medical School, Kochi University, Kochi 783-8505, Japan
| | - Katsuhito Kiyasu
- Department of Orthopedic Surgery, Kochi Medical School, Kochi University, Kochi 783-8505, Japan
| | - Kosuke Nakaji
- Department of Radiology, Kochi Medical School, Kochi University, Kochi 783-8505, Japan
| | - Masanori Daibata
- Department of Microbiology and Infection, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan
| | - Tetsuya Yamamoto
- Department of Oral and Maxillofacial Surgery, Kochi Medical School, Kochi University, Kochi 783-8505, Japan
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Xia XD, Alabi A, Wang M, Gu HM, Yang RZ, Wang G, Zhang DW. Membrane-type I matrix metalloproteinase (MT1-MMP), lipid metabolism and therapeutic implications. J Mol Cell Biol 2021; 13:513-526. [PMID: 34297054 PMCID: PMC8530520 DOI: 10.1093/jmcb/mjab048] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/04/2021] [Accepted: 06/14/2021] [Indexed: 11/13/2022] Open
Abstract
Lipids exert many essential physiological functions, such as serving as a structural component of biological membranes, storing energy, and regulating cell signal transduction. Dysregulation of lipid metabolism can lead to dyslipidemia related to various human diseases, such as obesity, diabetes, and cardiovascular disease. Therefore, lipid metabolism is strictly regulated through multiple mechanisms at different levels, including the extracellular matrix. Membrane-type I matrix metalloproteinase (MT1-MMP), a zinc-dependent endopeptidase, proteolytically cleaves extracellular matrix components, and non-matrix proteins, thereby regulating many physiological and pathophysiological processes. Emerging evidence supports the vital role of MT1-MMP in lipid metabolism. For example, MT1-MMP mediates ectodomain shedding of low-density lipoprotein receptor and increases plasma low-density lipoprotein cholesterol levels and the development of atherosclerosis. It also increases the vulnerability of atherosclerotic plaque by promoting collagen cleavage. Furthermore, it can cleave the extracellular matrix of adipocytes, affecting adipogenesis and the development of obesity. Therefore, the activity of MT1-MMP is strictly regulated by multiple mechanisms, such as autocatalytic cleavage, endocytosis and exocytosis, and post-translational modifications. Here, we summarize the latest advances in MT1-MMP, mainly focusing on its role in lipid metabolism, the molecular mechanisms regulating the function and expression of MT1-MMP, and their pharmacotherapeutic implications.
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Affiliation(s)
- Xiao-Dan Xia
- Department of Orthopedics, The Sixth Affiliated Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan 511500, China.,Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, T6R 2G3, Canada
| | - Adekunle Alabi
- Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, T6R 2G3, Canada
| | - Maggie Wang
- Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, T6R 2G3, Canada
| | - Hong-Mei Gu
- Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, T6R 2G3, Canada
| | - Rui Zhe Yang
- Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, T6R 2G3, Canada
| | - Guiqing Wang
- Department of Orthopedics, The Sixth Affiliated Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan 511500, China
| | - Da-Wei Zhang
- Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, T6R 2G3, Canada
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Molecular Changes on Maternal-Fetal Interface in Placental Abruption-A Systematic Review. Int J Mol Sci 2021; 22:ijms22126612. [PMID: 34205566 PMCID: PMC8235312 DOI: 10.3390/ijms22126612] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 06/14/2021] [Accepted: 06/17/2021] [Indexed: 12/21/2022] Open
Abstract
Placental abruption is the separation of the placenta from the lining of the uterus before childbirth. It is an infrequent perinatal complication with serious after-effects and a marked risk of maternal and fetal mortality. Despite the fact that numerous placental abruption risk factors are known, the pathophysiology of this issue is multifactorial and not entirely clear. The aim of this review was to examine the current state of knowledge concerning the molecular changes on the maternal–fetal interface occurring in placental abruption. Only original research articles describing studies published in English until the 15 March 2021 were considered eligible. Reviews, book chapters, case studies, conference papers and opinions were excluded. The systematic literature search of PubMed/MEDLINE and Scopus databases identified 708 articles, 22 of which were analyzed. The available evidence indicates that the disruption of the immunological processes on the maternal–fetal interface plays a crucial role in the pathophysiology of placental abruption. The features of chronic non-infectious inflammation and augmented immunological cytotoxic response were found to be present in placental abruption samples in the reviewed studies. Various molecules participate in this process, with only a few being examined. More advanced research is needed to fully explain this complicated process.
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Kumar D, Moore RM, Sharma A, Mercer BM, Mansour JM, Moore JJ. In an in-vitro model using human fetal membranes, α-lipoic acid inhibits inflammation induced fetal membrane weakening. Placenta 2018; 68:9-14. [PMID: 30055672 DOI: 10.1016/j.placenta.2018.06.305] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 06/04/2018] [Accepted: 06/18/2018] [Indexed: 12/20/2022]
Abstract
INTRODUCTION We established an in-vitro model for the study of human fetal membrane (FM) weakening leading to pPROM. In this model, granulocyte-macrophage colony-stimulating factor (GM-CSF) is a critical intermediate for both tumor necrosis factor-α (TNF; modeling infection/inflammation) and thrombin (modeling decidual bleeding/abruption)-induced weakening. Thus, inhibitors of FM weakening can be categorized as targeting GM-CSF production, GM-CSF downstream action, or both. Most progestogens inhibit both, except 17-α hydroxyprogesterone caproate which inhibits FM weakening at only one point, GM-CSF production. α-lipoic acid (LA), an over-the-counter dietary supplement, has also been previously shown to inhibit TNF and thrombin induced FM weakening. OBJECTIVE To determine the point of action of LA inhibition of FM weakening. METHODS FM fragments were mounted in Transwell inserts and preincubated with/without LA/24 h, then with/without addition of TNF, thrombin or GM-CSF. After 48 h, medium was assayed for GM-CSF, and FM fragments were rupture-strength tested. RESULTS TNF and thrombin both weakened FM and increased GM-CSF levels. GM-CSF also weakened FM. LA inhibited both TNF and thrombin induced FM weakening and concomitantly inhibited the increase in GM-CSF in a concentration-dependent manner. In addition, LA inhibited GM-CSF induced FM weakening in a concentration dependent manner. CONCLUSIONS LA blocks TNF and thrombin induced FM weakening at two points, inhibiting both GM-CSF production and downstream action. Thus, we speculate that LA may be a potential standalone therapeutic agent, or supplement to current therapy for prevention of pPROM related spontaneous preterm birth, if preclinical studies to examine feasibility and safety during pregnancy are successfully accomplished.
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Affiliation(s)
- Deepak Kumar
- Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA
| | - Robert M Moore
- Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA
| | - Anudeepa Sharma
- Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA
| | - Brian M Mercer
- Reproductive Biology, Case Western Reserve University, Cleveland, OH, USA
| | - Joseph M Mansour
- Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - John J Moore
- Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA; Reproductive Biology, Case Western Reserve University, Cleveland, OH, USA.
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In an in-vitro model using human fetal membranes, 17-α hydroxyprogesterone caproate is not an optimal progestogen for inhibition of fetal membrane weakening. Am J Obstet Gynecol 2017; 217:695.e1-695.e14. [PMID: 29031893 DOI: 10.1016/j.ajog.2017.10.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Revised: 09/25/2017] [Accepted: 10/02/2017] [Indexed: 02/02/2023]
Abstract
BACKGROUND The progestogen 17-α hydroxyprogesterone caproate (17-OHPC) is 1 of only 2 agents recommended for clinical use in the prevention of spontaneous preterm delivery, and studies of its efficacy have been conflicting. We have developed an in-vitro model to study the fetal membrane weakening process that leads to rupture in preterm premature rupture of the fetal membranes (pPROM). Inflammation/infection associated with tumor necrosis factor-α (TNF-α) induction and decidual bleeding/abruption associated thrombin release are leading causes of preterm premature rupture of the fetal membranes. Both agents (TNF-α and thrombin) cause fetal membrane weakening in the model system. Furthermore, granulocyte-macrophage colony-stimulating factor (GM-CSF) is a critical intermediate for both TNF-α and thrombin-induced fetal membrane weakening. In a previous report, we demonstrated that 3 progestogens, progesterone, 17-alpha hydroxyprogesterone (17-OHP), and medroxyprogesterone acetate (MPA), each inhibit both TNF-α- and thrombin-induced fetal membrane weakening at 2 distinct points of the fetal membrane weakening pathway. Each block both the production of and the downstream action of the critical intermediate granulocyte-macrophage colony-stimulating factor. OBJECTIVE The objective of the study was to characterize the inhibitory effects of 17-OHPC on TNF-α- and thrombin-induced fetal membrane weakening in vitro. STUDY DESIGN Full-thickness human fetal membrane fragments from uncomplicated term repeat cesarean deliveries were mounted in 2.5 cm Transwell inserts and cultured with/without 17-alpha hydroxyprogesterone caproate (10-9 to 10-7 M). After 24 hours, medium (supernatant) was removed and replaced with/without the addition of tumor necrosis factor-alpha (20 ng/mL) or thrombin (10 U/mL) or granulocyte-macrophage colony-stimulating factor (200 ng/mL). After 48 hours of culture, medium from the maternal side compartment of the model was assayed for granulocyte-macrophage colony-stimulating factor and the fetal membrane fragments were rupture strength tested. RESULTS Tumor necrosis factor-alpha and thrombin both weakened fetal membranes (43% and 62%, respectively) and increased granulocyte-macrophage colony-stimulating factor levels (3.7- and 5.9-fold, respectively). Pretreatment with 17-alpha hydroxyprogesterone caproate inhibited both tumor necrosis factor-alpha- and thrombin-induced fetal membrane weakening and concomitantly inhibited the induced increase in granulocyte-macrophage colony-stimulating factor in a concentration-dependent manner. However, contrary to our prior reports regarding progesterone and other progestogens, 17-alpha hydroxyprogesterone caproate did not also inhibit granulocyte-macrophage colony-stimulating factor-induced fetal membrane weakening. CONCLUSION 17-Alpha hydroxyprogesterone caproate blocks tumor necrosis factor-alpha- and thrombin-induced fetal membrane weakening by inhibiting the production of granulocyte-macrophage colony-stimulating factor. However, 17-alpha hydroxyprogesterone caproate did not also inhibit granulocyte-macrophage colony-stimulating factor-induced weakening. We speculate that progestogens other than 17-alpha hydroxyprogesterone caproate may be more efficacious in preventing preterm premature rupture of the fetal membranes-related spontaneous preterm birth.
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Expression of matrix metalloproteinase 2 (MMP-2), E-cadherin and Ki-67 in metastatic and non-metastatic canine mammary carcinomas. Ir Vet J 2016; 69:9. [PMID: 27486511 PMCID: PMC4969974 DOI: 10.1186/s13620-016-0068-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 07/26/2016] [Indexed: 11/28/2022] Open
Abstract
Background The aim of the study was to demonstrate the immunohistochemical expression of proteins that affect the metastatic potential of a tumour, including matrix metalloproteinase 2 (MMP-2) and E-cadherin. Another objective was to determine their correlation with the expression of the Ki-67 antigen in metastasizing and non-metastasizing mammary carcinomas in female dogs. The study was conducted on 32 canine mammary carcinomas (12 metastatic and 20 non-metastatic), classified as simple tubular and tubulopapillary carcinomas. Immunohistochemistry was performed to evaluate the expression of MMP-2, E-cadherin and Ki-67 antigen. Results MMP-2 was expressed in 85 % of the non-metastatic tumours and in all the metastatic tumours, while E-cadherin was expressed in 85 % of the non-metastatic tumours and in 66 % of the metastatic tumours. The Ki-67 antigen was expressed in 65 % of the non-metastatic tumours and in 91 % of the metastatic tumours. The mean Ki-67 expression was slightly higher in tumours that had metastasized (1.5 ± 0.90 vs 1.1 ± 0.94; p = 0.22). A similar relationship was found in terms of the intensity of the MMP-2 expression (2.9 ± 1.9 vs 2.7 ± 2.4; p = 0.50). A decrease in the expression of E-cadherin (2.8 ± 2.5) was found in metastatic tumours compared to the expression in non-metastatic tumours (3.2 ± 2.3). However, these differences were not statistically significant (p = 0.63). Conclusion We did not show significant differences in MMP-2, E-cadherin and Ki-67 expression between metastatic and non-metastatic tumours due to low number of cases studied, however further experiments are necessary to assess the role of these antigens in the process of canine mammary tumours metastasis.
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Hong IS. Stimulatory versus suppressive effects of GM-CSF on tumor progression in multiple cancer types. Exp Mol Med 2016; 48:e242. [PMID: 27364892 PMCID: PMC4973317 DOI: 10.1038/emm.2016.64] [Citation(s) in RCA: 161] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 03/11/2016] [Accepted: 03/23/2016] [Indexed: 12/18/2022] Open
Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF, also called CSF-2) is best known for its critical role in immune modulation and hematopoiesis. A large body of experimental evidence indicates that GM-CSF, which is frequently upregulated in multiple types of human cancers, effectively marks cancer cells with a ‘danger flag' for the immune system. In this context, most studies have focused on its function as an immunomodulator, namely its ability to stimulate dendritic cell (DC) maturation and monocyte/macrophage activity. However, recent studies have suggested that GM-CSF also promotes immune-independent tumor progression by supporting tumor microenvironments and stimulating tumor growth and metastasis. Although some studies have suggested that GM-CSF has inhibitory effects on tumor growth and metastasis, an even greater number of studies show that GM-CSF exerts stimulatory effects on tumor progression. In this review, we summarize a number of findings to provide the currently available information regarding the anticancer immune response of GM-CSG. We then discuss the potential roles of GM-CSF in the progression of multiple types of cancer to provide insights into some of the complexities of its clinical applications.
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Affiliation(s)
- In-Sun Hong
- Laboratory of Stem Cell Research, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea.,Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, South Korea
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de Bruyn M, Vandooren J, Ugarte-Berzal E, Arijs I, Vermeire S, Opdenakker G. The molecular biology of matrix metalloproteinases and tissue inhibitors of metalloproteinases in inflammatory bowel diseases. Crit Rev Biochem Mol Biol 2016; 51:295-358. [PMID: 27362691 DOI: 10.1080/10409238.2016.1199535] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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The physiology of fetal membrane weakening and rupture: Insights gained from the determination of physical properties revisited. Placenta 2016; 42:59-73. [PMID: 27238715 DOI: 10.1016/j.placenta.2016.03.015] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 03/05/2016] [Accepted: 03/31/2016] [Indexed: 01/14/2023]
Abstract
Rupture of the fetal membranes (FM) is precipitated by stretch forces acting upon biochemically mediated, pre-weakened tissue. Term FM develop a para-cervical weak zone, characterized by collagen remodeling and apoptosis, within which FM rupture is thought to initiate. Preterm FM also have a weak region but are stronger overall than term FM. Inflammation/infection and decidual bleeding/abruption are strongly associated with preterm premature FM rupture (pPROM), but the specific mechanisms causing FM weakening-rupture in pPROM are unknown. There are no animal models for study of FM weakening and rupture. Over a decade ago we developed equipment and methodology to test human FM strength and incorporated it into a FM explant system to create an in-vitro human FM weakening model system. Within this model TNF (modeling inflammation) and Thrombin (modeling bleeding) both weaken human FM with concomitant up regulation of MMP9 and cellular apoptosis, mimicking the characteristics of the spontaneous FM rupture site. The model has been enhanced so that test agents can be applied directionally to the choriodecidual side of the FM explant consistent with the in-vivo situation. With this enhanced system we have demonstrated that the pathways involving inflammation/TNF and bleeding/Thrombin induced FM weakening overlap. Furthermore GM-CSF production was demonstrated to be a critical common intermediate step in both the TNF and the Thrombin induced FM weakening pathways. This model system has also been used to test potential inhibitors of FM weakening and therefore pPROM. The dietary supplement α-lipoic acid and progestogens (P4, MPA and 17α-hydroxyprogesterone) have been shown to inhibit both TNF and Thrombin induced FM weakening. The progestogens act at multiple points by inhibiting both GM-CSF production and GM-CSF action. The use of a combined biomechanical/biochemical in-vitro human FM weakening model system has allowed the pathways of fetal membrane weakening to be delineated, and agents that may be of clinical use in inhibiting these pathways to be tested.
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LNA aptamer based multi-modal, Fe3O4-saturated lactoferrin (Fe3O4-bLf) nanocarriers for triple positive (EpCAM, CD133, CD44) colon tumor targeting and NIR, MRI and CT imaging. Biomaterials 2015; 71:84-99. [PMID: 26318819 DOI: 10.1016/j.biomaterials.2015.07.055] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Revised: 07/29/2015] [Accepted: 07/31/2015] [Indexed: 12/28/2022]
Abstract
This is the first ever attempt to combine anti-cancer therapeutic effects of emerging anticancer biodrug bovine lactoferrin (bLf), and multimodal imaging efficacy of Fe3O4 nanoparticles (NPs) together, as a saturated Fe3O4-bLf. For cancer stem cell specific uptake of nanocapsules/nanocarriers (NCs), Fe3O4-bLf was encapsulated in alginate enclosed chitosan coated calcium phosphate (AEC-CP) NCs targeted (Tar) with locked nucleic acid (LNA) modified aptamers against epithelial cell adhesion molecule (EpCAM) and nucleolin markers. The nanoformulation was fed orally to mice injected with triple positive (EpCAM, CD133, CD44) sorted colon cancer stem cells in the xenograft cancer stem cell mice model. The complete regression of tumor was observed in 70% of mice fed on non-targeted (NT) NCs, with 30% mice showing tumor recurrence after 30 days, while only 10% mice fed with Tar NCs showed tumor recurrence indicating a significantly higher survival rate. From tumor tissue analyses of 35 apoptotic markers, 55 angiogenesis markers, 40 cytokines, 15 stem cell markers and gene expression studies of important signaling molecules, it was revealed that the anti-cancer mechanism of Fe3O4-bLf was intervened through TRAIL, Fas, Fas-associated protein with death domain (FADD) mediated phosphorylation of p53, to induce activation of second mitochondria-derived activator of caspases (SMAC)/DIABLO (inhibiting survivin) and mitochondrial depolarization leading to release of cytochrome C. Induction of apoptosis was observed by inhibition of the Akt pathway and activation of cytokines released from monocytes/macrophages and dendritic cells (interleukin (IL) 27, keratinocyte chemoattractant (KC)). On the other hand, the recurrence of tumor in AEC-CP-Fe3O4-bLf NCs fed mice mainly occurred due to activation of alternative pathways such as mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinases (ERK) and Wnt signaling leading to an increase in expression of survivin, survivin splice variant (survivin 2B) and other anti-apoptotic proteins Bad, Bcl-2 and XIAP. Apart from the promising anti-cancer efficacy and the exceptional tumor targeting ability observed by multimodal imaging using near-infrared (NIR) imaging, magnetic resonance imaging (MRI) and computerized tomographic (CT) techniques, these NCs also maintained the immunomodulatory benefits of bLf as they were able to increase the RBC, hemoglobin, iron calcium and zinc levels in mice.
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Kumar D, Moore RM, Nash A, Springel E, Mercer BM, Philipson E, Mansour JM, Moore JJ. Decidual GM-CSF is a critical common intermediate necessary for thrombin and TNF induced in-vitro fetal membrane weakening. Placenta 2014; 35:1049-56. [PMID: 25454284 DOI: 10.1016/j.placenta.2014.10.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Revised: 09/26/2014] [Accepted: 10/03/2014] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Inflammation/infection and decidual bleeding/abruption are highly associated with pPROM. As no animal model for pPROM exists, we have developed an in-vitro model system for the study of human fetal membrane (FM) weakening/rupture. Using it we have demonstrated that both TNF/IL-1 (modeling inflammation) and thrombin (modeling bleeding) weaken full thickness FM in a dose dependent manner concomitant with inducing biochemical changes similar to those seen in the FM physiological weak zone. METHODS As the physiological site of infection and bleeding is the choriodecidua (CD), we modified our model system with full thickness FM tissue mounted on modified Transwell culture inserts to permit directional TNF/thrombin exposure on the decidua only (rather than both sides of the FM). After incubation, medium was sampled separately from the CD facing (maternal side) or from the amnion facing (fetal side) compartments and probed for cytokine release and confirmed with western blots. The FM was strength tested within the insert. RESULTS Full-thickness FM fragments exposed to TNF or thrombin on CD side only showed dose dependent weakening and biochemical changes consistent with previous reports. Concomitantly, GM-CSF increased markedly on the CD but not the amnion side. Numerous proteases including MMP1 and MMP3 also increased on the CD side. Pre-incubation with GM-CSF antibody blocked both thrombin and TNF induced weakening. Finally, GM-CSF weakened FM in a dose dependent manner. DISCUSSION GM-CSF is a critical common intermediate in the thrombin and TNF FM weakening pathways.
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Affiliation(s)
- D Kumar
- Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA.
| | - R M Moore
- Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA
| | - A Nash
- Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA
| | - E Springel
- Department of Reproductive Biology, Case Western Reserve University, Cleveland, OH, USA
| | - B M Mercer
- Department of Reproductive Biology, Case Western Reserve University, Cleveland, OH, USA
| | - E Philipson
- Women's Institute-Cleveland Clinic, Cleveland, OH, USA
| | - J M Mansour
- Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - J J Moore
- Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA; Department of Reproductive Biology, Case Western Reserve University, Cleveland, OH, USA
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Gutschalk CM, Yanamandra AK, Linde N, Meides A, Depner S, Mueller MM. GM-CSF enhances tumor invasion by elevated MMP-2, -9, and -26 expression. Cancer Med 2012; 2:117-29. [PMID: 23634280 PMCID: PMC3639651 DOI: 10.1002/cam4.20] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Revised: 06/17/2012] [Accepted: 06/18/2012] [Indexed: 12/11/2022] Open
Abstract
Granulocyte–macrophage colony-stimulating factor (GM-CSF) promotes tumor progression in different tumor models in an autocrine and paracrine manner. However, at the same time GM-CSF is used in cancer therapies to ameliorate neutropenia. We have previously shown in GM-CSF and G-CSF expressing or negative skin or head and neck squamous cell carcinoma that GM-CSF expression is associated with a highly angiogenic and invasive tumor phenotype. To determine the functional contribution of GM-CSF to tumor invasion, we stably transfected a GM-CSF negative colon adenocarcinoma cell line HT-29 with GM-CSF or treated the same cell line with exogenous GM-CSF. While GM-CSF overexpression and treatment reduced tumor cell proliferation and tumor growth in vitro and in vivo, respectively, it contributed to tumor progression. Together with an enhanced migratory capacity in vitro, we observed a striking increase in tumor cell invasion into the surrounding tissue concomitant with the induction of an activated tumor stroma in GM-CSF overexpressing or GM-CSF treated tumors. In a complex 3D in vitro model, enhanced GM-CSF expression was associated with a discontinued basement membrane deposition that might be mediated by the increased expression and activation of MMP-2, -9, and -26. Treatment with GM-CSF blocking antibodies reversed this effect. The increased presence and activity of these tumor cell derived proteases was confirmed in vivo. Here, expression of MMP-26 protein was predominantly located in pre- and early-invasive areas suggesting MMP-26 expression as an early event in promoting GM-CSF dependent tumor invasion.
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Affiliation(s)
- Claudia M Gutschalk
- Group of Tumor and Microenvironment, German Cancer Research Center (DKFZ) Heidelberg, Germany
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Riau AK, Wong TT, Finger SN, Chaurasia SS, Hou AH, Chen S, Yu SJ, Tong L. Aberrant DNA methylation of matrix remodeling and cell adhesion related genes in pterygium. PLoS One 2011; 6:e14687. [PMID: 21359202 PMCID: PMC3040179 DOI: 10.1371/journal.pone.0014687] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2009] [Accepted: 01/22/2011] [Indexed: 11/18/2022] Open
Abstract
Background Pterygium is a common ocular surface disease characterized by abnormal epithelial and fibrovascular proliferation, invasion, and matrix remodeling. This lesion, which migrates from the periphery to the center of the cornea, impairs vision and causes considerable irritation. The mechanism of pterygium formation remains ambiguous, and current treatment is solely surgical excision, with a significant risk of recurrence after surgery. Here, we investigate the role of methylation in DNA sequences that regulate matrix remodeling and cell adhesion in pterygium formation. Methodology/Principal Findings Pterygium and uninvolved conjunctiva samples were obtained from the same eye of patients undergoing surgery. The EpiTYPER Sequenom technology, based on differential base cleavage and bisulfite sequencing was used to evaluate the extent of methylation of 29 matrix and adhesion related genes. In pterygium, three CpG sites at −268, −32 and −29 bp upstream of transglutaminase 2 (TGM-2) transcription initiation were significantly hypermethylated (p<0.05), whereas hypomethylation was detected at CpGs +484 and +602 bp downstream of matrix metalloproteinase 2 (MMP-2) transcription start site, and −809, −762, −631 and −629 bp upstream of the CD24 transcription start site. RT-qPCR, western blot and immunofluorescent staining showed that transcript and protein expression were reduced for TGM-2 and increased for MMP-2 and CD24. Inhibition of methylation in cultured conjunctival epithelial cells increased these transcripts. Conclusions/Significance We found regions of aberrant DNA methylation which were consistent with alteration of TGM-2, MMP-2, and CD24 transcript and protein expression, and that inhibition of methylation in cultured cells can increase the expression of these genes. Since these genes were related to cell adhesion and matrix remodeling, dysregulation may lead to fibroblastic and neovascular changes and pterygium formation. These results have implications for the prognostication of pterygium in clinical practice, for example, detection of epigenetic changes may have a role in predicting post surgical recurrence of aggressive lesions.
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Affiliation(s)
- Andri K. Riau
- Ocular Wound Healing and Therapeutics Laboratory, Singapore Eye Research Institute, Singapore, Singapore
| | - Tina T. Wong
- Ocular Wound Healing and Therapeutics Laboratory, Singapore Eye Research Institute, Singapore, Singapore
- Singapore National Eye Center, Singapore, Singapore
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- School of Materials Science and Engineering, Nanyang Technological University, Singapore, Singapore
| | - Sharon N. Finger
- Ocular Wound Healing and Therapeutics Laboratory, Singapore Eye Research Institute, Singapore, Singapore
| | - Shyam S. Chaurasia
- Ocular Wound Healing and Therapeutics Laboratory, Singapore Eye Research Institute, Singapore, Singapore
| | - Ai Hua Hou
- Ocular Wound Healing and Therapeutics Laboratory, Singapore Eye Research Institute, Singapore, Singapore
| | - Silin Chen
- Ocular Wound Healing and Therapeutics Laboratory, Singapore Eye Research Institute, Singapore, Singapore
| | - Shang Juan Yu
- Ocular Wound Healing and Therapeutics Laboratory, Singapore Eye Research Institute, Singapore, Singapore
| | - Louis Tong
- Ocular Wound Healing and Therapeutics Laboratory, Singapore Eye Research Institute, Singapore, Singapore
- Singapore National Eye Center, Singapore, Singapore
- Duke-NUS Graduate Medical School, Singapore, Singapore
- * E-mail:
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Chung AS, Kao WJ. Fibroblasts regulate monocyte response to ECM-derived matrix: The effects on monocyte adhesion and the production of inflammatory, matrix remodeling, and growth factor proteins. J Biomed Mater Res A 2009; 89:841-53. [DOI: 10.1002/jbm.a.32431] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Krubasik D, Eisenach PA, Kunz-Schughart LA, Murphy G, English WR. Granulocyte-macrophage colony stimulating factor induces endothelial capillary formation through induction of membrane-type 1 matrix metalloproteinase expression in vitro. Int J Cancer 2008; 122:1261-72. [PMID: 18027871 DOI: 10.1002/ijc.23234] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
In our study, we examined the mechanism by which granulocyte-macrophage colony stimulating factor (GM-CSF) regulates angiogenesis using in vitro models. GM-CSF significantly increased precapillary sprout-like formation from endothelial cell spheroids seeded in type-I collagen gels and tubule formation on coculture of endothelial cells with fibroblasts. In both cases, sprout and tubule formation was highly dependent on metalloproteinase activity. Tissue Inhibitor of metalloproteinase (TIMP) profiling in the spheroid and coculture models showed inhibition by TIMP-2 but not by TIMP-1, indicative of activity of membrane-type matrix metalloproteinases (MT-MMPs). GM-CSF induced sprout formation in spheroids was found to be potently inhibited by siRNA specific for MT1-MMP. Subsequent analysis showed that GM-CSF transiently increased MT1-MMP mRNA in endothelial cells in a MEK-dependent mechanism, which led to increased surface levels of MT1-MMP. This was accompanied by an increase in MT1-MMP-dependent degradation of DQ-collagen by lysates of GM-CSF stimulated endothelial cells. GM-CSF did not increase MT1-MMP levels in fibroblasts. The effect of GM-CSF on endothelial cell sprout formation could be mimicked by adenoviral transduction of intact spheroids with virus expressing MT1-MMP, but not by transduction of endothelial cells before spheroid formation, suggesting that upregulation of MT1-MMP must only occur in cells directly involved in tubule formation.
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Affiliation(s)
- Davia Krubasik
- Cancer Research UK, Cambridge Research Institute, Cambridge, United Kingdom
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Gutschalk CM, Herold-Mende CC, Fusenig NE, Mueller MM. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor promote malignant growth of cells from head and neck squamous cell carcinomas in vivo. Cancer Res 2007; 66:8026-36. [PMID: 16912178 DOI: 10.1158/0008-5472.can-06-0158] [Citation(s) in RCA: 100] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are used to ameliorate cancer therapy-induced neutropenia and mucositis. Yet, first data in head and neck squamous cell carcinoma (HNSCC) indicate an impaired long-term prognosis on G-CSF treatment, and previous studies showed a contribution of both factors to the progression of human epithelial tumors. Therefore, we investigate the role of G-CSF and GM-CSF in progression of tumor cells from human HNSCC. Both factors stimulated proliferation and migration of tumor cell lines established from patient tumors expressing G-CSF and GM-CSF and/or their receptors. Blockade of G-CSF and GM-CSF inhibited tumor cell invasion in a three-dimensional organotypic culture model. The contribution of both factors to tumor malignancy was further confirmed in nude mouse transplants in vivo. Invasive and malignant growth yielding a similar tumor phenotype as the original patient tumor was exclusively observed in G-CSF- and GM-CSF-expressing tumors and was associated with enhanced and persistent angiogenesis and enhanced inflammatory cell recruitment. Although factor-negative tumors grew somewhat faster, they were characterized by lack of invasion, reduced and transient angiogenesis, and large necrotic areas. These data provide evidence for a progression-promoting effect of G-CSF and GM-CSF in human HNSCC and suggest further detailed evaluation of their use in the therapy of these tumors.
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Affiliation(s)
- Claudia M Gutschalk
- Group of Tumour and Microenvironment, German Cancer Research Centre, Heidelberg, Germany
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Skrzydlewska E, Sulkowska M, Koda M, Sulkowski S. Proteolytic-antiproteolytic balance and its regulation in carcinogenesis. World J Gastroenterol 2005; 11:1251-66. [PMID: 15761961 PMCID: PMC4250670 DOI: 10.3748/wjg.v11.i9.1251] [Citation(s) in RCA: 122] [Impact Index Per Article: 6.1] [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
Cancer development is essentially a tissue remodeling process in which normal tissue is substituted with cancer tissue. A crucial role in this process is attributed to proteolytic degradation of the extracellular matrix (ECM). Degradation of ECM is initiated by proteases, secreted by different cell types, participating in tumor cell invasion and increased expression or activity of every known class of proteases (metallo-, serine-, aspartyl-, and cysteine) has been linked to malignancy and invasion of tumor cells. Proteolytic enzymes can act directly by degrading ECM or indirectly by activating other proteases, which then degrade the ECM. They act in a determined order, resulting from the order of their activation. When proteases exert their action on other proteases, the end result is a cascade leading to proteolysis. Presumable order of events in this complicated cascade is that aspartyl protease (cathepsin D) activates cysteine proteases (e.g., cathepsin B) that can activate pro-uPA. Then active uPA can convert plasminogen into plasmin. Cathepsin B as well as plasmin are capable of degrading several components of tumor stroma and may activate zymogens of matrix metalloproteinases, the main family of ECM degrading proteases. The activities of these proteases are regulated by a complex array of activators, inhibitors and cellular receptors. In physiological conditions the balance exists between proteases and their inhibitors. Proteolytic-antiproteolytic balance may be of major significance in the cancer development. One of the reasons for such a situation is enhanced generation of free radicals observed in many pathological states. Free radicals react with main cellular components like proteins and lipids and in this way modify proteolytic-antiproteolytic balance and enable penetration damaging cellular membrane. All these lead to enhancement of proteolysis and destruction of ECM proteins and in consequence to invasion and metastasis.
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Affiliation(s)
- Elzbieta Skrzydlewska
- Department of Analytical Chemistry, Medical University of Bialystok, Mickiewicza 2, 15-230 Bialystok, Poland.
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Klein G, Vellenga E, Fraaije MW, Kamps WA, de Bont ESJM. The possible role of matrix metalloproteinase (MMP)-2 and MMP-9 in cancer, e.g. acute leukemia. Crit Rev Oncol Hematol 2004; 50:87-100. [PMID: 15157658 DOI: 10.1016/j.critrevonc.2003.09.001] [Citation(s) in RCA: 277] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/01/2003] [Indexed: 12/12/2022] Open
Abstract
In the past decades, a lot of effort has been put in identifying the role of matrix metalloproteinases (MMPs) in cancer. The main role of MMPs in angiogenesis, tumor growth and metastasis is degradation of extracellular matrix (ECM) and release and/or activation of growth factors through their degradative activity. The degradative activity finally results in cancer progression. MMP-inhibitors (MMPIs) have already been designed and tested, based on the degradative role of MMPs in cancer progression. First clinical trials with MMPIs have been performed with disappointing results, showing that in order to use MMP-inhibition the mechanisms underlying MMP-expression in cancer have to be further elucidated. This paper reviews the mechanisms of MMPs on molecular and cellular level and discusses the role for MMPs and MMP-inhibition in cancer with special focus on acute leukemia.
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Affiliation(s)
- G Klein
- Division of Pediatric Oncology and Hematology, Beatrix Children's Hospital, Groningen University Hospital, Hanzeplein 1, P.O. Box 30.001, Groningen 9700 RB, The Netherlands
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Ninck S, Reisser C, Dyckhoff G, Helmke B, Bauer H, Herold-Mende C. Expression profiles of angiogenic growth factors in squamous cell carcinomas of the head and neck. Int J Cancer 2003; 106:34-44. [PMID: 12794754 DOI: 10.1002/ijc.11188] [Citation(s) in RCA: 97] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Inhibition of angiogenesis by blocking angiogenic cytokines or their pathways has become a major target in experimental cancer therapies. This therapeutical approach requires a profound knowledge of growth factor profiles that contribute to tumor growth and progression. The respective knowledge is presently rather incomplete for head and neck squamous cell carcinomas (HNSCC). Therefore we studied expression of several angiogenic cytokines including VEGF, bFGF, PDGF-AB, PDGF-BB, G-CSF and GM-CSF in HNSCC in vivo and in vitro. In tumor tissues expression of all cytokines was observed albeit with marked differences concerning intensity and distribution pattern. Quantification of the cytokines in the supernatant of 15 tissue-corresponding HNSCC cultures revealed that VEGF, PDGF-AB and less frequently GM-CSF were secreted in high amounts of up to 13 ng/ml/10(6) cells. Twenty percent of the HNSCC cultures expressed only 1 cytokine in biologically active amounts, 60% 2 or 3 and 20% expressed the maximum of 4 cytokines simultaneously. Interestingly, we observed a distinct cytokine pattern: HNSCC cells secreting only 1 or 2 cytokines presented always with either VEGF and/or PDGF-AB, while G-CSF and GM-CSF were secreted primarily together with VEGF and PDGF-AB. The number of cytokines expressed by HNSCC cells correlated with the microvessel density of the original tumor and with the clinical outcome: tumors producing at least 3 cytokines revealed a significantly poorer patient prognosis. Our data indicate a major role for VEGF and PDGF-AB in HNSCC and that the additional secretion of G-CSF or GM-CSF might contribute to a poorer prognosis in patients suffering from these tumors.
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Affiliation(s)
- Simon Ninck
- Department of Head and Neck Surgery, University of Heidelberg, Germany
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Plenz G, Eschert H, Beissert S, Arps V, Sindermann JR, Robenek H, Völker W. Alterations in the vascular extracellular matrix of granulocyte macrophage colony-stimulating factor (GM-CSF) -deficient mice. FASEB J 2003; 17:1451-7. [PMID: 12890699 DOI: 10.1096/fj.02-1035com] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
GM-CSF takes part in the cytokine network regulating the metabolism of extracellular matrix (ECM) during atherogenesis. Since data also point to an effect of GM-CSF on the vascular ECM in general, the vascular collagenous matrix was studied in wild-type and GM-CSF-deficient mice. Histological examination revealed a disorganized vascular ECM in GM-CSF-deficient mice involving the collagenous matrix and elastic fiber system. As shown by electron microscopy, collagen bundles were disrupted and reduced. The diameter of fibrils varied widely. mRNA expression of collagens and related molecules was studied. Fibrillar collagens were markedly reduced, alpha1(I)procollagen to 16.5% of control levels alpha1(III)procollagen was abolished whereas the expression level of network-forming alpha1(VIII)procollagen was not altered. As shown by in situ hybridization, the number of collagen-expressing cells was reduced. Matrix metalloproteinases and their inhibitor 1 were not affected by GM-CSF deficiency. Our studies demonstrate that GM-CSF plays a major role in the cytokine network regulating the metabolism of vascular collagens. GM-CSF deficiency leads to an altered composition of the vascular collagenous matrix, i.e., reduced amount of fibrillar collagen, altered ratio of fibrillar and network-forming collagen, and failures in the fibrillogenesis. We suggest that GM-CSF is a basic requirement for the maintenance of vessel wall integrity and resilience.
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Affiliation(s)
- Gabriele Plenz
- Institute for Arteriosclerosis Research, Domagkstr. 3, D-48149 Münster, Germany.
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Adair-Kirk TL, Atkinson JJ, Broekelmann TJ, Doi M, Tryggvason K, Miner JH, Mecham RP, Senior RM. A site on laminin alpha 5, AQARSAASKVKVSMKF, induces inflammatory cell production of matrix metalloproteinase-9 and chemotaxis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2003; 171:398-406. [PMID: 12817023 DOI: 10.4049/jimmunol.171.1.398] [Citation(s) in RCA: 86] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Several peptide sequences in laminin alpha1, the alpha-chain of laminin (Ln)-1, mediate biological responses in vitro, but Ln-1 is rare in vivo. Since Ln-5 and Ln-10, which contain the alpha3 and alpha5 chains, respectively, are the most prominent laminin heterotrimers in normal adult tissues and few functional domains in other laminin chains have been identified, we are investigating the alpha3 and alpha5 chains for biological activities. Incubation of mouse macrophages with the laminin alpha5 peptide AQARSAASKVKVSMKF resulted in marked increase in matrix metalloproteinase (MMP)-9 mRNA and gelatinolytic activity in the conditioned media, whereas the corresponding alpha3 peptide QQARDAANKVAIPMRF had no effect. AQARSAASKVKVSMKF also induced expression of MMP-14, while MMP-2, MMP-3, MMP-7, MMP-12, and MMP-13 were not induced by this peptide. Deletion analyses indicated that a minimal sequence of ASKVKVSMKF was sufficient for increasing MMP-9 expression. AQARSAASKVKVSMKF was also chemotactic for neutrophils and macrophages in vitro, and induced accumulation of neutrophils and macrophages in lung airspaces in vivo following intranasal instillation into mice. Comparable accumulation occurred in MMP-9-deficient mice, indicating that MMP-9 was not required for AQARSAASKVKVSMKF-induced inflammatory cell emigration in the lung. A scrambled version of the minimal peptide, KAKSFVMVSK, was inactive. These data indicate that laminin alpha5-derived peptides can induce inflammatory cell chemotaxis and metalloproteinase activity.
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Affiliation(s)
- Tracy L Adair-Kirk
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, MO 63110, USA
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Plenz GAM, Deng MC, Robenek H, Völker W. Vascular collagens: spotlight on the role of type VIII collagen in atherogenesis. Atherosclerosis 2003; 166:1-11. [PMID: 12482545 DOI: 10.1016/s0021-9150(01)00766-3] [Citation(s) in RCA: 84] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Collagens play a central role in maintaining the integrity and stability of the undiseased as well as of the atherosclerotic vessel wall. An imbalanced metabolism may lead to uncontrolled collagen accumulation reducing vessel wall velocity, frequently resulting in arterial occlusion or thrombosis. A reduced production of collagen and its uncontrolled degradation may affect the stability of the vessel wall and especially of the atherosclerotic plaques by making them prone to rupture and aneurysm. This review presents an overview on the four groups of vascular collagens and on their role in atherogenesis. The major focus was to highlight the extraordinary role and importance of the short chain network forming type VIII collagen in the extracellular matrix of undiseased arteries and of atherosclerotic plaques. The molecular structure of type VIII collagen, its cellular origin, its implication in atherogenesis, its temporal and spatial expression patterns in human and experimental models of atherogenesis, the factors modulating its expression, and--not at least--its potential function is discussed.
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Affiliation(s)
- Gabriele A M Plenz
- Department of Cell Biology and Ultrastructure Research, Institute for Arteriosclerosis Research, Domagkstr. 3, 48149 Münster, Germany.
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Myoung H, Kim MJ, Hong SD, Lee JI, Lim CY, Hong SP. Expression of membrane type I-matrix metalloproteinase in oral squamous cell carcinoma. Cancer Lett 2002; 185:201-9. [PMID: 12169394 DOI: 10.1016/s0304-3835(02)00281-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
A local invasion and lymph node metastasis (LNM) of an oral squamous cell carcinoma (OSCC) has a poor prognosis, and involves the degradation of the extracellular matrix mediated by multiple proteolytic enzymes including membrane type I-matrix metalloproteinase (MT1-MMP). This study aimed to determine the role of MT1-MMP in OSCC, to evaluate the immunohistochemical expression of MT1-MMP with regard to the invasiveness and LNM of the OSCC, and to evaluate the major source of MT1-MMP mRNA and its protein using immunohistochemistry and in situ hybridization. MT1-MMP expression was examined in 46 OSCCs via immunohistochemistry and non-radioisotope in situ hybridization. The relationship between MT1-MMP expression and LNM, as well as the histological invasiveness, was statistically analyzed. The results showed that whereas 12 out of the 18 OSCCs (66.7%) with LNM showed moderate to strong MT1-MMP expression, only nine of the 28 OSCCs (32.1%) without LNM expressed MT1-MMP strongly. MT1-MMP expression was significantly higher with regard to LNM (P=0.022). As the invasion grade became stronger (from grade a to grade d), MT1-MMP was significantly more strongly expressed (P=0.033). These results suggest that MT1-MMP is primarily secreted in the OSCC cells and is involved in the invasiveness of the OSCC and LNM. Moreover, MT1-MMP combined with other markers may be used to predict the metastatic potential of an OSCC.
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Affiliation(s)
- Hoon Myoung
- Department of Oral Pathology, Dental Research Institute, College of Dentistry, Seoul National University, 28-2 Yeongun-Dong, Chongno-Ku, 110-749, Seoul, South Korea
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Watanabe H, Iwase M, Ohashi M, Nagumo M. Role of interleukin-8 secreted from human oral squamous cell carcinoma cell lines. Oral Oncol 2002; 38:670-9. [PMID: 12167419 DOI: 10.1016/s1368-8375(02)00006-4] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Interleukin-8 (IL-8) is an important cytokine involved in tumor growth and angiogenesis in a variety of malignancies. Furthermore, matrix metalloptoteinases (MMPs) also play important roles in the invasion and metastasis of carcinomas including oral squamous cell carcinoma (OSCC). We studied whether IL-8 and MMPs participate in tumorigenesis and metastasis of OSCC. First, we investigated the gene and protein expressions of IL-8 and IL-8 receptor (IL-8R), and the effect of IL-8 on proliferation, migration and invasion of OSCC. Second, we thus also investigated the effect of IL-8 on MMP release in OSCC cells. OSCC cell lines NA and HSC-4 constitutively expressed IL-8 mRNA and secreted its protein in vitro. The production of IL-8 was significantly enhanced by the addition of tumor necrosis factor (TNF)-alpha and IL-beta, but not interferon (IFN)-gamma, granulocyte-macrophage colony-stimulating factor (GM-CSF) or IL-2. Flow cytometric analysis revealed the constitutive expression of both receptors of IL-8, IL-8RA and IL-8RB, in OSCC cell lines. The expression of IL-8 receptors in HSC-4 cells was stronger than that in NA cells. The intensity of IL-8RA expression was stronger than that of IL-8RB expression in each cell line. The expression of IL-8 receptors was not altered by the addition of cytokines such as TNF-alpha and IL-1beta. The conditioned medium containing IL-8 from OSCC cell lines induced migration and invasion of OSCC cells, but did not change cell proliferation. The differences in migrational and invasive ability between NA cells and HSC-4 cells were correlated with the expression intensity of IL-8 receptors in each cell line. Neutralizing antibodies to IL-8, IL-8RA and IL-8RB partially inhibited the chemotactic activity induced by conditioned medium. The expression of MMP-2, -7 and -9 was detected in culture supernatants from these OSCC cell lines. The expressions of MMP-7 protein and mRNA were enhanced by the addition of rIL-8, but that of other MMPs was not observed in a similar manner. These results suggest that IL-8 secreted from OSCC may contribute to the invasion of OSCC through the regulation of MMP-7 expression.
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Affiliation(s)
- H Watanabe
- Second Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, Tokyo 145-8515, Japan
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