{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T19:18:27Z","timestamp":1790968707767,"version":"4.1.0"},"reference-count":127,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T00:00:00Z","timestamp":1616716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["F99AG068527"],"award-info":[{"award-number":["F99AG068527"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1CA109545"],"award-info":[{"award-number":["RO1CA109545"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UO1CA236797"],"award-info":[{"award-number":["UO1CA236797"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Proteases play a crucial role in the progression and metastasis of ovarian cancer. Pericellular protein degradation and fragmentation along with remodeling of the extracellular matrix (ECM) is accomplished by numerous proteases that are present in the ovarian tumor microenvironment. Several proteolytic processes have been linked to cancer progression, particularly those facilitated by the matrix metalloproteinase (MMP) family. These proteases have been linked to enhanced migratory ability, extracellular matrix breakdown, and development of support systems for tumors. Several studies have reported the direct involvement of MMPs with ovarian cancer, as well as their mechanisms of action in the tumor microenvironment. MMPs play a key role in upregulating transcription factors, as well as the breakdown of structural proteins like collagen. Proteolytic mechanisms have been shown to enhance the ability of ovarian cancer cells to migrate and adhere to secondary sites allowing for efficient metastasis. Furthermore, angiogenesis for tumor growth and development of metastatic implants is influenced by upregulation of certain proteases, including MMPs. While proteases are produced normally in vivo, they can be upregulated by cancer-associated mutations, tumor\u2013microenvironment interaction, stress-induced catecholamine production, and age-related pathologies. This review outlines the important role of proteases throughout ovarian cancer progression and metastasis.<\/jats:p>","DOI":"10.3390\/ijms22073403","type":"journal-article","created":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T06:59:42Z","timestamp":1616741982000},"page":"3403","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["Metalloproteinases in Ovarian Cancer"],"prefix":"10.3390","volume":"22","author":[{"given":"Preston","family":"Carey","sequence":"first","affiliation":[{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA"},{"name":"Department of Preprofessional Studies, University of Notre Dame, Notre Dame, IN 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan","family":"Low","sequence":"additional","affiliation":[{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA"},{"name":"Department of Chemistry &amp; Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3547-1692","authenticated-orcid":false,"given":"Elizabeth","family":"Harper","sequence":"additional","affiliation":[{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA"},{"name":"Department of Chemistry &amp; Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA"},{"name":"Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4563-7390","authenticated-orcid":false,"given":"M. Sharon","family":"Stack","sequence":"additional","affiliation":[{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA"},{"name":"Department of Chemistry &amp; Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,26]]},"reference":[{"key":"ref_1","unstructured":"Howlader, N., Noone, A.M., Krapcho, M., Miller, D., Brest, A., Yu, M., Ruhl, J., Tatalovich, Z., Mariotto, A., and Lewis, D.R. (2020, November 01). SEER Cancer Statistics Review, 1975\u20132017, Available online: https:\/\/seer.cancer.gov\/csr\/1975_2017\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.canlet.2016.04.038","article-title":"Tumor microenvironment: The culprit for ovarian cancer metastasis?","volume":"377","author":"Luo","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1007\/978-0-387-98094-2_15","article-title":"Microenvironmental Regulation of Ovarian Cancer Metastasis","volume":"149","author":"Barbolina","year":"2009","journal-title":"Cancer Treat. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1002\/ijc.22874","article-title":"Use of a novel 3D culture model to elucidate the role of mesothelial cells, fibroblasts and extra-cellular matrices on adhesion and invasion of ovarian cancer cells to the omentum","volume":"121","author":"Kenny","year":"2007","journal-title":"Int. J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"30433","DOI":"10.1074\/jbc.R800035200","article-title":"Proteases: Multifunctional Enzymes in Life and Disease","volume":"283","author":"Bond","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_6","unstructured":"Antalis, T.M., and Bugge, T. (2009). Proteases and Cancer. Methods and Protocols, Humana Press."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"R55","DOI":"10.1530\/REP-14-0546","article-title":"Ovarian cancer: Involvement of the matrix metalloproteinases","volume":"150","author":"Curry","year":"2015","journal-title":"Reproduction"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e6104","DOI":"10.1590\/1414-431x20176104","article-title":"Relationship between matrix metalloproteinases and the occurrence and development of ovarian cancer","volume":"50","author":"Zhang","year":"2017","journal-title":"Br. J. Med. Biol. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3853","DOI":"10.1007\/s00018-011-0763-x","article-title":"Matrix metalloproteinases in tumorigenesis: An evolving paradigm","volume":"68","author":"Hua","year":"2011","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/nrm2125","article-title":"Matrix metalloproteinases and the regulation of tissue remodelling","volume":"8","author":"Ewald","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.cardiores.2005.12.002","article-title":"Structure and function of matrix metalloproteinases and TIMPs","volume":"69","author":"Nagase","year":"2006","journal-title":"Cardiovasc. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1200\/JCO.2000.18.5.1135","article-title":"Matrix Metalloproteinases: Biologic Activity and Clinical Implications","volume":"18","author":"Nelson","year":"2000","journal-title":"J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4924","DOI":"10.1074\/jbc.M608428200","article-title":"Microenvironmental Regulation of Membrane Type 1 Matrix Metalloproteinase Activity in Ovarian Carcinoma Cells via Collagen-induced EGR1 Expression","volume":"282","author":"Barbolina","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3619","DOI":"10.1038\/onc.2013.321","article-title":"Epithelial ovarian cancer experimental models","volume":"33","author":"Lengyel","year":"2013","journal-title":"Oncogene"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5840","DOI":"10.1038\/onc.2017.171","article-title":"Cadherin composition and multicellular aggregate invasion in organotypic models of epithelial ovarian cancer intraperitoneal metastasis","volume":"36","author":"Klymenko","year":"2017","journal-title":"Oncogene"},{"key":"ref_16","first-page":"150","article-title":"Membrane-type matrix metalloproteinase expression and matrix metalloproteinase-2 activation in primary human ovarian epithelial carcinoma cells","volume":"16","author":"Fishman","year":"1996","journal-title":"Invasion Metastasis"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7121","DOI":"10.1158\/0008-5472.CAN-08-4151","article-title":"Ovarian Cancer Cell Detachment and Multicellular Aggregate Formation Are Regulated by Membrane Type 1 Matrix Metalloproteinase: A Potential Role in I.p. Metastatic Dissemination","volume":"69","author":"Moss","year":"2009","journal-title":"Cancer Res."},{"key":"ref_18","first-page":"1635","article-title":"Ovarian carcinoma regulation of matrix metalloproteinase-2 and membrane type 1 matrix metalloproteinase through beta1 integrin","volume":"59","author":"Ellerbroek","year":"1999","journal-title":"Cancer Res."},{"key":"ref_19","first-page":"2396","article-title":"Increased expression of matrix metalloproteinases (MMP)-2, MMP-9, and the urokinase-type plasminogen activator is associated with progression from benign to advanced ovarian cancer","volume":"7","author":"Schmalfeldt","year":"2001","journal-title":"Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1006\/gyno.2001.6243","article-title":"Expression of Latent Matrix Metalloproteinase 9 (MMP-9) Predicts Survival in Advanced Ovarian Cancer","volume":"82","author":"Lengyel","year":"2001","journal-title":"Gynecol. Oncol."},{"key":"ref_21","first-page":"123","article-title":"Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability","volume":"436","author":"Radisky","year":"2005","journal-title":"Nat. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1172\/JCI33775","article-title":"The initial steps of ovarian cancer cell metastasis are mediated by MMP-2 cleavage of vitronectin and fibronectin","volume":"118","author":"Kenny","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"683","DOI":"10.4161\/cc.8.5.7703","article-title":"MMP-2 functions as an early response protein in ovarian cancer metastasis","volume":"8","author":"Kenny","year":"2009","journal-title":"Cell Cycle"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"177","DOI":"10.3109\/14756366.2016.1161620","article-title":"Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs","volume":"31","author":"Matejczyk","year":"2016","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0092-8674(00)81683-9","article-title":"The Hallmarks of Cancer","volume":"100","author":"Hanahan","year":"2000","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.matbio.2015.04.004","article-title":"Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature","volume":"44\u201346","author":"Deryugina","year":"2015","journal-title":"Matrix Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1038\/nm1447","article-title":"Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma","volume":"12","author":"Thaker","year":"2006","journal-title":"Nat. Med."},{"key":"ref_28","first-page":"461","article-title":"Involvement of TNF-alpha in enhancement of invasion and metastasis of colon 26-L5 carcinoma cells in mice by social isolation stress","volume":"11","author":"Wu","year":"1999","journal-title":"Oncol. Res. Featur. Preclin. Clin. Cancer Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.2353\/ajpath.2010.100105","article-title":"Ovarian Cancer Development and Metastasis","volume":"177","author":"Lengyel","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1093\/jnci\/95.6.484","article-title":"Mutations in BRAF and KRAS Characterize the Development of Low-Grade Ovarian Serous Carcinoma","volume":"95","author":"Singer","year":"2003","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1016\/S0002-9440(10)63708-X","article-title":"Ovarian Tumorigenesis","volume":"164","author":"Shih","year":"2004","journal-title":"Am. J. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"76881","DOI":"10.18632\/oncotarget.20173","article-title":"PAX2 maintains the differentiation of mouse oviductal epithelium and inhibits the transition to a stem cell-like state","volume":"8","author":"Alwosaibai","year":"2017","journal-title":"Oncotarget"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/cr.2009.5","article-title":"TGF-\u03b2-induced epithelial to mesenchymal transition","volume":"19","author":"Xu","year":"2009","journal-title":"Cell Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11387","DOI":"10.1073\/pnas.1000500107","article-title":"Ouabain modulates epithelial cell tight junction","volume":"107","author":"Larre","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.1091\/mbc.e05-07-0650","article-title":"Zonula Occludens-1 Function in the Assembly of Tight Junctions in Madin-Darby Canine Kidney Epithelial Cells","volume":"17","author":"McNeil","year":"2006","journal-title":"Mol. Biol. Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1038\/sj.emboj.7600136","article-title":"E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases","volume":"23","author":"Qian","year":"2004","journal-title":"EMBO J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1083\/jcb.142.4.1105","article-title":"Mechanisms of Epithelial Cell\u2013Cell Adhesion and Cell Compaction Revealed by High-resolution Tracking of E-Cadherin\u2013 Green Fluorescent Protein","volume":"142","author":"Adams","year":"1998","journal-title":"J. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s00441-011-1281-8","article-title":"Protein myozap\u2014A late addition to the molecular ensembles of various kinds of adherens junctions","volume":"346","author":"Rickelt","year":"2011","journal-title":"Cell Tissue Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"51553","DOI":"10.18632\/oncotarget.9928","article-title":"Motility and stem cell properties induced by the epithelial-mesenchymal transition require destabilization of lipid rafts","volume":"7","author":"Tisza","year":"2016","journal-title":"Oncotarget"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1172\/JCI39104","article-title":"The basics of epithelial-mesenchymal transition","volume":"119","author":"Kalluri","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5506","DOI":"10.1021\/la404832t","article-title":"Modeling Persistence in Mesenchymal Cell Motility Using Explicit Fibers","volume":"30","author":"Lepzelter","year":"2014","journal-title":"Langmuir"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1002\/ijc.2910560415","article-title":"Secretion of extracellular matrix-degrading proteinases is increased in epithelial ovarian carcinoma","volume":"56","author":"Moser","year":"1994","journal-title":"Int. J. Cancer"},{"key":"ref_43","first-page":"417","article-title":"Expression of the metalloproteinase matrilysin in DU-145 cells increases their invasive potential in severe combined immunodeficient mice","volume":"53","author":"Powell","year":"1993","journal-title":"Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1111\/j.1349-7006.2011.01861.x","article-title":"Matrix metalloproteinase-9 cooperates with transcription factor Snail to induce epithelial-mesenchymal transition","volume":"102","author":"Lin","year":"2011","journal-title":"Cancer Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3328","DOI":"10.1074\/jbc.275.5.3328","article-title":"Truncation of the \u03b2-Catenin Binding Domain of E-cadherin Precedes Epithelial Apoptosis during Prostate and Mammary Involution","volume":"275","author":"Vallorosi","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.1158\/0008-5472.CAN-06-2808","article-title":"Engagement of Collagen-Binding Integrins Promotes Matrix Metalloproteinase-9\u2013Dependent E-Cadherin Ectodomain Shedding in Ovarian Carcinoma Cells","volume":"67","author":"Symowicz","year":"2007","journal-title":"Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1042\/BJ20120053","article-title":"SP-1 regulation of MMP-9 expression requires Ser586 in the PEST domain","volume":"445","author":"Murthy","year":"2012","journal-title":"Biochem. J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1158\/1078-0432.CCR-05-2686","article-title":"Tumor Epithelial Cell Matrix Metalloproteinase 9 Is a Target for Antimetastatic Therapy in Colorectal Cancer","volume":"12","author":"Lubbe","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"21903","DOI":"10.1038\/srep21903","article-title":"Simultaneous knockdown of uPA and MMP9 can reduce breast cancer progression by increasing cell-cell adhesion and modulating EMT genes","volume":"6","author":"Moirangthem","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Rosso, M., Majem, B., Devis, L., Lapyckyj, L., Besso, M.J., Llaurad\u00f3, M., Abascal, M.F., Matos, M.L., Lanau, L., and Castellv\u00ed, J. (2017). E-cadherin: A determinant molecule associated with ovarian cancer progression, dissemination and aggressiveness. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0184439"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1038\/sj.bjc.6601685","article-title":"Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells","volume":"90","author":"Miyoshi","year":"2004","journal-title":"Br. J. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1006\/gyno.2000.6042","article-title":"Regulation of Invasion of Epithelial Ovarian Cancer by Transforming Growth Factor-\u03b2","volume":"80","author":"Rodriguez","year":"2001","journal-title":"Gynecol. Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.canlet.2014.08.015","article-title":"A novel \u03b2-catenin signaling pathway activated by IL-1\u03b2 leads to the onset of epithelial\u2013mesenchymal transition in breast cancer cells","volume":"354","author":"Lezama","year":"2014","journal-title":"Cancer Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1083\/jcb.139.7.1861","article-title":"Matrix Metalloproteinase Stromelysin-1 Triggers a Cascade of Molecular Alterations That Leads to Stable Epithelial-to-Mesenchymal Conversion and a Premalignant Phenotype in Mammary Epithelial Cells","volume":"139","author":"Lochter","year":"1997","journal-title":"J. Cell Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"6883","DOI":"10.1007\/s13277-015-3381-7","article-title":"Decreased MT1-MMP in gastric cancer suppressed cell migration and invasion via regulating MMPs and EMT","volume":"36","author":"Li","year":"2015","journal-title":"Tumor Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"13111","DOI":"10.1074\/jbc.M117.800904","article-title":"Post-translational modification of the membrane type 1 matrix metalloproteinase (MT1-MMP) cytoplasmic tail impacts ovarian cancer multicellular aggregate dynamics","volume":"292","author":"Yang","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1515\/hsz-2014-0155","article-title":"Membrane-type I matrix metalloproteinase-dependent ectodomain shedding of mucin16\/ CA-125 on ovarian cancer cells modulates adhesion and invasion of peritoneal mesothelium","volume":"395","author":"Bruney","year":"2014","journal-title":"Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1056\/NEJM198310133091503","article-title":"A Radioimmunoassay Using a Monoclonal Antibody to Monitor the Course of Epithelial Ovarian Cancer","volume":"309","author":"Bast","year":"1983","journal-title":"N. Engl. J. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"9190","DOI":"10.1074\/jbc.M312372200","article-title":"Binding of Ovarian Cancer Antigen CA125\/MUC16 to Mesothelin Mediates Cell Adhesion","volume":"279","author":"Rump","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.ygyno.2011.02.020","article-title":"MUC16 (CA125) regulates epithelial ovarian cancer cell growth, tumorigenesis and metastasis","volume":"121","author":"Pinard","year":"2011","journal-title":"Gynecol. Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Jiao, Y., Feng, X., Zhan, Y., Wang, R., Zheng, S., Liu, W., and Zeng, X. (2012). Matrix metalloproteinase-2 Promotes \u03b1v\u03b23 Integrin-Mediated Adhesion and Migration of Human Melanoma Cells by Cleaving Fibronectin. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041591"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"24833","DOI":"10.1074\/jbc.M005631200","article-title":"Functional Interplay between Type I Collagen and Cell Surface Matrix Metalloproteinase Activity","volume":"276","author":"Ellerbroek","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Xu, K. (2016). Ovarian Cancer Metastasis: A Unique Mechanism of Dissemination. Tumor Metastasis, InTech.","DOI":"10.5772\/61798"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5923","DOI":"10.1038\/onc.2015.43","article-title":"Microenvironment-induced downregulation of miR-193b drives ovarian cancer metastasis","volume":"34","author":"Mitra","year":"2015","journal-title":"Oncogene"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"3747","DOI":"10.1242\/jcs.029769","article-title":"Signaling through urokinase and urokinase receptor in lung cancer cells requires interactions with beta1 integrins","volume":"121","author":"Tang","year":"2008","journal-title":"J. Cell Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3937","DOI":"10.1038\/onc.2009.245","article-title":"Downregulation of miR-193b contributes to enhance urokinase-type plasminogen activator (uPA) expression and tumor progression and invasion in human breast cancer","volume":"28","author":"Li","year":"2009","journal-title":"Oncogene"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.ygyno.2009.04.031","article-title":"Expression of urokinase plasminogen activator and its receptor in advanced epithelial ovarian cancer patients","volume":"114","author":"Wang","year":"2009","journal-title":"Gynecol. Oncol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"39","DOI":"10.2174\/1381612043453559","article-title":"The Urokinase Plasminogen Activator System: Role in Malignancy","volume":"10","author":"Duffy","year":"2004","journal-title":"Curr. Pharm. Des."},{"key":"ref_69","first-page":"e379","article-title":"Adaptation of ovarian cancer cells to the peritoneal environment: Multiple mechanisms of the developmental patterning gene HOXA9","volume":"1","author":"Ko","year":"2014","journal-title":"Cancer Cell Microenviron."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3603","DOI":"10.1172\/JCI62229","article-title":"HOXA9 promotes ovarian cancer growth by stimulating cancer-associated fibroblasts","volume":"122","author":"Ko","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1158\/0008-5472.CAN-12-1426","article-title":"Selective Blockade of Matrix Metalloprotease-14 with a Monoclonal Antibody Abrogates Invasion, Angiogenesis, and Tumor Growth in Ovarian Cancer","volume":"73","author":"Kaimal","year":"2013","journal-title":"Cancer Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1006\/gyno.1996.0195","article-title":"Characterization of Gelatinases Linked to Extracellular Matrix Invasion in Ovarian Adenocarcinoma: Purification of Matrix Metalloproteinase 2","volume":"62","author":"Young","year":"1996","journal-title":"Gynecol. Oncol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1002\/(SICI)1097-0142(19971015)80:8<1457::AID-CNCR13>3.0.CO;2-4","article-title":"Production of extracellular matrix-degrading proteinases by primary cultures of human epithelial ovarian carcinoma cells","volume":"80","author":"Fishman","year":"1997","journal-title":"Cancer"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"19791","DOI":"10.1074\/jbc.M109.020362","article-title":"Modulation of the Membrane Type 1 Matrix Metalloproteinase Cytoplasmic Tail Enhances Tumor Cell Invasion and Proliferation in Three-dimensional Collagen Matrices","volume":"284","author":"Moss","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2473","DOI":"10.1056\/NEJMoa1104390","article-title":"Incorporation of Bevacizumab in the Primary Treatment of Ovarian Cancer","volume":"365","author":"Burger","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"i33","DOI":"10.1093\/annonc\/mdw093","article-title":"Anti-angiogenic agents in ovarian cancer: Past, present, and future","volume":"27","author":"Monk","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/S0015-0282(00)00670-1","article-title":"Role of vascular endothelial growth factor in ovarian physiology and pathology","volume":"74","author":"Geva","year":"2000","journal-title":"Fertil. Steril."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1002\/cncr.20449","article-title":"Vascular endothelial growth factor C and vascular endothelial growth factor receptor 2 are related closely to the prognosis of patients with ovarian carcinoma","volume":"101","author":"Nishida","year":"2004","journal-title":"Cancer"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/S0002-9440(10)64873-0","article-title":"Vascular Endothelial Growth Factor-165 Overexpression Stimulates Angiogenesis and Induces Cyst Formation and Macrophage Infiltration in Human Ovarian Cancer Xenografts","volume":"160","author":"Duyndam","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_80","first-page":"1854","article-title":"VEGF(121), VEGF(165) overexpression enhances tumorigenicity in U251 MG but not in NG-1 glioma cells","volume":"62","author":"Ke","year":"2002","journal-title":"Cancer Res."},{"key":"ref_81","first-page":"3403","article-title":"Tumor-derived vascular endothelial growth factor up-regulates angiopoietin-2 in host endothelium and destabilizes host vasculature, supporting angiogenesis in ovarian cancer","volume":"63","author":"Zhang","year":"2003","journal-title":"Cancer Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1111\/j.1523-1755.2005.67101.x","article-title":"Autocrine and paracrine functions of vascular endothelial growth factor (VEGF) in renal tubular epithelial cells","volume":"67","author":"Villegas","year":"2005","journal-title":"Kidney Int."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3884","DOI":"10.1073\/pnas.97.8.3884","article-title":"Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model","volume":"97","author":"Fang","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_84","first-page":"1048","article-title":"Reduced angiogenesis and tumor progression in gelatinase A-deficient mice","volume":"58","author":"Itoh","year":"1998","journal-title":"Cancer Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"37491","DOI":"10.1074\/jbc.M104094200","article-title":"Membrane Type 1-Matrix Metalloproteinase Is Activated during Migration of Human Endothelial Cells and Modulates Endothelial Motility and Matrix Remodeling","volume":"276","author":"Albar","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/S0092-8674(00)81169-1","article-title":"MMP-9\/Gelatinase B is a Key Regulator of Growth Plate Angiogenesis and Apoptosis of Hypertrophic Chondrocytes","volume":"93","author":"Vu","year":"1998","journal-title":"Cell"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"4052","DOI":"10.1073\/pnas.060037197","article-title":"Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I","volume":"97","author":"Zhou","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1093\/jnci\/94.15.1134","article-title":"Contributions of Stromal Metalloproteinase-9 to Angiogenesis and Growth of Human Ovarian Carcinoma in Mice","volume":"94","author":"Huang","year":"2002","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_89","first-page":"580","article-title":"Up-regulation of vascular endothelial growth factor by membrane-type 1 matrix metalloproteinase stimulates human glioma xenograft growth and angiogenesis","volume":"62","author":"Deryugina","year":"2002","journal-title":"Cancer Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1096\/fj.01-0790com","article-title":"MT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression","volume":"16","author":"Sounni","year":"2002","journal-title":"FASEB J."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"13564","DOI":"10.1074\/jbc.M307688200","article-title":"Up-regulation of Vascular Endothelial Growth Factor-A by Active Membrane-type 1 Matrix Metalloproteinase through Activation of Src-Tyrosine Kinases","volume":"279","author":"Sounni","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1038\/35036374","article-title":"Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis","volume":"2","author":"Bergers","year":"2000","journal-title":"Nat. Cell Biol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1158\/1541-7786.MCR-07-0366","article-title":"Vascular Endothelial Growth Factor Stimulates Organ-Specific Host Matrix Metalloproteinase-9 Expression and Ovarian Cancer Invasion","volume":"6","author":"Belotti","year":"2008","journal-title":"Mol. Cancer Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1182\/blood-2009-08-239426","article-title":"VEGF\/VEGFR2 interaction down-regulates matrix metalloproteinase\u20139 via STAT1 activation and inhibits B chronic lymphocytic leukemia cell migration","volume":"115","author":"Eroles","year":"2010","journal-title":"Blood"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1002\/ijc.25134","article-title":"MMP-2 alters VEGF expression via \u03b1V\u03b23 integrin-mediated PI3K\/AKT signaling in A549 lung cancer cells","volume":"127","author":"Chetty","year":"2009","journal-title":"Int. J. Cancer"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1083\/jcb.200103111","article-title":"Proteolytic exposure of a cryptic site within collagen type IV is required for angiogenesis and tumor growth in vivo","volume":"154","author":"Xu","year":"2001","journal-title":"J. Cell Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"7788","DOI":"10.1074\/jbc.271.13.7788","article-title":"The Carboxyl-terminal Domain(111\u2013165) of Vascular Endothelial Growth Factor Is Critical for Its Mitogenic Potency","volume":"271","author":"Keyt","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_98","first-page":"4514","article-title":"Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines","volume":"9","author":"Lutgendorf","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1158\/1078-0432.CCR-05-1698","article-title":"Stress Hormone\u2013Mediated Invasion of Ovarian Cancer Cells","volume":"12","author":"Sood","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.bbi.2010.10.012","article-title":"Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients","volume":"25","author":"Lutgendorf","year":"2011","journal-title":"Brain Behav. Immun."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1002\/cncr.10739","article-title":"Vascular endothelial growth factor and social support in patients with ovarian carcinoma","volume":"95","author":"Lutgendorf","year":"2002","journal-title":"Cancer"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"10357","DOI":"10.1158\/0008-5472.CAN-06-2496","article-title":"Norepinephrine Up-regulates the Expression of Vascular Endothelial Growth Factor, Matrix Metalloproteinase (MMP)-2, and MMP-9 in Nasopharyngeal Carcinoma Tumor Cells","volume":"66","author":"Yang","year":"2006","journal-title":"Cancer Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/S0165-5728(02)00270-9","article-title":"Stress-related modulation of matrix metalloproteinase expression","volume":"133","author":"Yang","year":"2002","journal-title":"J. Neuroimmunol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1023\/A:1024491219366","article-title":"Effects of Neurotransmitters on the Chemokinesis and Chemotaxis of MDA-MB-468 Human Breast Carcinoma Cells","volume":"80","author":"Drell","year":"2003","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_105","first-page":"2866","article-title":"Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by beta-blockers","volume":"61","author":"Masur","year":"2001","journal-title":"Cancer Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"5597","DOI":"10.1210\/endo.137.12.8940389","article-title":"Immobilization stress elevates gene expression for catecholamine biosynthetic enzymes and some neuropeptides in rat sympathetic ganglia: Effects of adrenocorticotropin and glucocorticoids","volume":"137","author":"Nankova","year":"1996","journal-title":"Endocrinology"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1385\/ENDO:8:3:309","article-title":"Stress Promotes Development of Ovarian Cysts in Rats: The Possible Role of Sympathetic Nerve Activation","volume":"8","author":"Paredes","year":"1998","journal-title":"Endocrine"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1385\/ENDO:15:2:187","article-title":"Release of Norepinephrine from Human Ovary: Coupling to Steroidogenic Response","volume":"15","author":"Lara","year":"2001","journal-title":"Endocrine"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"10990","DOI":"10.1073\/pnas.95.18.10990","article-title":"Oocytes are a source of catecholamines in the primate ovary: Evidence for a cell-cell regulatory loop","volume":"95","author":"Mayerhofer","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"6839","DOI":"10.1158\/1078-0432.CCR-08-0230","article-title":"Biobehavioral Influences on Matrix Metalloproteinase Expression in Ovarian Carcinoma","volume":"14","author":"Lutgendorf","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/nrc1256","article-title":"Tumour-educated macrophages promote tumour progression and metastasis","volume":"4","author":"Pollard","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.neo.2018.03.007","article-title":"Aging Increases Susceptibility to Ovarian Cancer Metastasis in Murine Allograft Models and Alters Immune Composition of Peritoneal Adipose Tissue","volume":"20","author":"Loughran","year":"2018","journal-title":"Neoplasia"},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Harper, E.I., Sheedy, E.F., and Stack, M.S. (2018). With Great Age Comes Great Metastatic Ability: Ovarian Cancer and the Appeal of the Aging Peritoneal Microenvironment. Cancers, 10.","DOI":"10.3390\/cancers10070230"},{"key":"ref_114","first-page":"3299","article-title":"Elevated levels of proteolytic enzymes in the aging human vitreous","volume":"41","author":"Gilbert","year":"2000","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2776","DOI":"10.1073\/pnas.84.9.2776","article-title":"Limited cleavage of cellular fibronectin by plasminogen activator purified from transformed cells","volume":"84","author":"Quigley","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2012\/564259","article-title":"Cell Surface Remodeling by Plasmin: A New Function for an Old Enzyme","volume":"2012","author":"Deryugina","year":"2012","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1242\/jcs.01635","article-title":"Stromal-epithelial interactions in aging and cancer: Senescent fibroblasts alter epithelial cell differentiation","volume":"118","author":"Parrinello","year":"2005","journal-title":"J. Cell Sci."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1056\/NEJM199711133372003","article-title":"Pathophysiology of Premature Skin Aging Induced by Ultraviolet Light","volume":"337","author":"Fisher","year":"1997","journal-title":"N. Engl. J. Med."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1111\/j.1749-6632.2002.tb04602.x","article-title":"Ultraviolet-B Irradiation and Matrix Metalloproteinases","volume":"973","author":"Brenneisen","year":"2002","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/jidsymp.2009.8","article-title":"Matrix-Degrading Metalloproteinases in Photoaging","volume":"14","author":"Quan","year":"2009","journal-title":"J. Investig. Dermatol. Symp. Proc."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S0014-5793(97)00175-0","article-title":"Involvement of PA\/plasmin system in the processing of pro-MMP-9 and in the second step of pro-MMP-2 activation","volume":"405","author":"Baramova","year":"1997","journal-title":"FEBS Lett."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/sj.bjc.6603863","article-title":"MT1-MMP is the critical determinant of matrix degradation and invasion by ovarian cancer cells","volume":"97","author":"Sodek","year":"2007","journal-title":"Br. J. Cancer"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1182\/blood.V97.8.2323","article-title":"Growth factor\u2013induced angiogenesis in vivo requires specific cleavage of fibrillar type I collagen","volume":"97","author":"Seandel","year":"2001","journal-title":"Blood"},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Mahner, S., Woelber, L., Eulenburg, C., Schwarz, J., Carney, W., Jaenicke, F., Milde-Langosch, K., and Mueller, V. (2010). TIMP-1 and VEGF-165 serum concentration during first-line therapy of ovarian cancer patients. BMC Cancer, 10.","DOI":"10.1186\/1471-2407-10-139"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1111\/bph.14186","article-title":"Monoclonal antibodies against metzincin targets","volume":"176","author":"Santamaria","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1158\/0008-5472.CAN-08-3255","article-title":"Selective Inhibition of Matrix Metalloproteinase-14 Blocks Tumor Growth, Invasion, and Angiogenesis","volume":"69","author":"Devy","year":"2009","journal-title":"Cancer Res."},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Ager, E.I., Kozin, S.V., Kirkpatrick, N.D., Seano, G., Kodack, D.P., Askoxylakis, V., Huang, Y., Goel, S., Snuderl, M., and Muzikansky, A. (2015). Blockade of MMP14 Activity in Murine Breast Carcinomas: Implications for Macrophages, Vessels, and Radiotherapy. J. Natl. Cancer Inst., 107.","DOI":"10.1093\/jnci\/djv017"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/7\/3403\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:41:21Z","timestamp":1760161281000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/7\/3403"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,26]]},"references-count":127,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["ijms22073403"],"URL":"https:\/\/doi.org\/10.3390\/ijms22073403","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,26]]}}}