{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:25:33Z","timestamp":1783297533704,"version":"3.54.6"},"reference-count":42,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T00:00:00Z","timestamp":1683244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Education, Science, Sports and Culture, Japan","award":["17K09741"],"award-info":[{"award-number":["17K09741"]}]},{"name":"Ministry of Education, Science, Sports and Culture, Japan","award":["24590336"],"award-info":[{"award-number":["24590336"]}]},{"name":"Ministry of Education, Science, Sports and Culture, Japan","award":["21590295"],"award-info":[{"award-number":["21590295"]}]},{"name":"Ministry of Education, Science, Sports and Culture, Japan","award":["15590240"],"award-info":[{"award-number":["15590240"]}]},{"name":"Ministry of Education, Science, Sports and Culture, Japan","award":["13670102"],"award-info":[{"award-number":["13670102"]}]},{"name":"Ministry of Education, Science, Sports and Culture, Japan","award":["20K08601"],"award-info":[{"award-number":["20K08601"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>It has long been known that high-grade mucoepidermoid carcinoma (MEC) has a poor prognosis, but the detailed molecular and biological mechanisms underlying this are not fully understood. In the present study, the pattern of chymase-positive mast cells, as well as chymase gene expression, in high-grade MEC was compared to that of low-grade and intermediate-grade MEC by using 44 resected tumor samples of MEC of the parotid gland. Chymase expression, as well as chymase-positive mast cells, was found to be markedly increased in high-grade MEC. Significant increases in PCNA-positive cells and VEGF gene expression, as well as lymphangiogenesis, were also confirmed in high-grade MEC. Chymase substrates, such as the latent transforming growth factor-beta (TGF-\u03b2) 1 and pro-matrix metalloproteinase (MMP)-9, were also detected immunohistologically in high-grade MEC. These findings suggested that the increased chymase activity may increase proliferative activity, as well as metastasis in the malignant condition, and the inhibition of chymase may be a strategy to improve the poor prognosis of high-grade MEC of the parotid gland.<\/jats:p>","DOI":"10.3390\/ijms24098267","type":"journal-article","created":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T03:24:32Z","timestamp":1683257072000},"page":"8267","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Increased Chymase-Positive Mast Cells in High-Grade Mucoepidermoid Carcinoma of the Parotid Gland"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6061-3114","authenticated-orcid":false,"given":"Hiromi","family":"Nishimura","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology\u2014Head and Neck Surgery, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5820-8168","authenticated-orcid":false,"given":"Denan","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Innovative Medicine, Graduate School of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4721-3121","authenticated-orcid":false,"given":"Ichita","family":"Kinoshita","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology\u2014Head and Neck Surgery, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7379-5065","authenticated-orcid":false,"given":"Masataka","family":"Taniuchi","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology\u2014Head and Neck Surgery, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaaki","family":"Higashino","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology\u2014Head and Neck Surgery, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6449-1468","authenticated-orcid":false,"given":"Tetsuya","family":"Terada","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology\u2014Head and Neck Surgery, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6196-4477","authenticated-orcid":false,"given":"Shinji","family":"Takai","sequence":"additional","affiliation":[{"name":"Department of Innovative Medicine, Graduate School of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Kawata","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology\u2014Head and Neck Surgery, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1002\/hed.21706","article-title":"Diagnosis and management of parotid carcinoma with a special focus on recent advances in molecular biology","volume":"34","author":"Bradley","year":"2012","journal-title":"Head Neck."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1002\/1097-0142(19920415)69:8<2021::AID-CNCR2820690803>3.0.CO;2-7","article-title":"Mucoepidermoid carcinoma of intraoral salivary glands. Evaluation and application of grading criteria in 143 cases","volume":"69","author":"Auclair","year":"1992","journal-title":"Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1002\/(SICI)1097-0142(19980401)82:7<1217::AID-CNCR2>3.0.CO;2-C","article-title":"Mucoepidermoid carcinoma of the major salivary glands: Clinical and histopathologic analysis of 234 cases with evaluation of grading criteria","volume":"82","author":"Goode","year":"1998","journal-title":"Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3928","DOI":"10.1002\/cncr.26697","article-title":"Prognostic factors in mucoepidermoid carcinoma of the salivary glands","volume":"118","author":"McHugh","year":"2012","journal-title":"Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1002\/cncr.23825","article-title":"Treatment and survival outcomes based on histologic grading in patients with head and neck mucoepidermoid carcinoma","volume":"113","author":"Nance","year":"2008","journal-title":"Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Kinoshita, I., Jin, D., Higashino, M., Terada, T., Kurisu, Y., Takai, S., and Kawata, R. (2021). Increase in Chymase-Positive Mast Cells in Recurrent Pleomorphic Adenoma and Carcinoma Ex Pleomorphic Adenoma of the Parotid Gland. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222312613"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1002\/jso.20394","article-title":"Expression of chymase-positive cells in gastric cancer and its correlation with the angiogenesis","volume":"93","author":"Kondo","year":"2006","journal-title":"J. Surg. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.ejcts.2005.06.020","article-title":"The relationship of tryptase- and chymase-positive mast cells to angiogenesis in stage I non-small cell lung cancer","volume":"28","author":"Ibaraki","year":"2005","journal-title":"Eur. J. Cardio-Thorac. Surg."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1097\/00004872-198406000-00010","article-title":"Evidence for a putatively new angiotensin II-generating enzyme in the vascular wall","volume":"2","author":"Okunishi","year":"1984","journal-title":"J. Hypertens."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/0024-3205(95)02328-3","article-title":"Purification and characterization of angiotensin II-generating chymase from hamster cheek pouch","volume":"58","author":"Takai","year":"1996","journal-title":"Life Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1096\/fj.00-0273com","article-title":"Activation of paracrine TGF-beta1 signaling upon stimulation and degranulation of rat serosal mast cells: A novel function for chymase","volume":"15","author":"Lindstedt","year":"2001","journal-title":"FASEB J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1172\/JCI118583","article-title":"Dog mastocytoma cells secrete a 92-kD gelatinase activated extracellularly by mast cell chymase","volume":"97","author":"Fang","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1016\/j.immuni.2019.03.024","article-title":"Transforming Growth Factor-beta Signaling in Immunity and Cancer","volume":"50","author":"Batlle","year":"2019","journal-title":"Immunity"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"856831","DOI":"10.3389\/fonc.2022.856831","article-title":"Epidemiological Evidence Between Variants in Matrix Metalloproteinases-2, -7, and -9 and Cancer Risk","volume":"12","author":"Huang","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1038\/sj.bjp.0704893","article-title":"Suppression of basic fibroblast growth factor-induced angiogenesis by a specific chymase inhibitor, BCEAB, through the chymase-angiotensin-dependent pathway in hamster sponge granulomas","volume":"137","author":"Muramatsu","year":"2002","journal-title":"Br. J. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1023\/A:1023470709071","article-title":"Mechanics of vimentin intermediate filaments","volume":"23","author":"Wang","year":"2002","journal-title":"J. Muscle. Res. Cell. Motil."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1016\/S0002-9440(10)62353-X","article-title":"Regulation of alpha-smooth muscle actin expression in granulation tissue myofibroblasts is dependent on the intronic CArG element and the transforming growth factorbeta1 control element","volume":"166","author":"Tomasek","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3727","DOI":"10.1038\/s41598-021-81796-2","article-title":"Characterising cancer-associated fibroblast heterogeneity in non-small cell lung cancer: A systematic review and meta-analysis","volume":"11","author":"Irvine","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1177\/37.10.2674273","article-title":"Detection of MCT and MCTC types of human mast cells by immunohistochemistry using new monoclonal anti-tryptase and anti-chymase antibodies","volume":"37","author":"Irani","year":"1989","journal-title":"J. Histochem. Cytochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.acthis.2016.05.002","article-title":"Ki67, PCNA, and MCM proteins: Markers of proliferation in the diagnosis of breast cancer","volume":"118","author":"Danihel","year":"2016","journal-title":"Acta Histochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3552","DOI":"10.1002\/1097-0142(19930601)71:11<3552::AID-CNCR2820711115>3.0.CO;2-N","article-title":"Prediction of Early Relapse and Shortened Survival in Patients with Breast Cancer by Proliferating Cell Nuclear Antigen Score","volume":"71","author":"Tahan","year":"1993","journal-title":"Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"833","DOI":"10.3892\/or.2015.4070","article-title":"Podoplanin is involved in the prognosis of head and neck squamous cell carcinoma through interaction with VEGF-C","volume":"34","author":"Kim","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1097\/01.LAB.0000028824.03032.AB","article-title":"A new monoclonal antibody, D2-40, for detection of lymphatic invasion in primary tumors","volume":"82","author":"Kahn","year":"2002","journal-title":"Lab Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1111\/jth.14976","article-title":"Von Willebrand factor and cancer; metastasis and coagulopathies","volume":"18","author":"Patmore","year":"2020","journal-title":"J. Thromb. Haemost."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/nrendo.2014.114","article-title":"VEGF-targeted cancer therapeutics-paradoxical effects in endocrine organs","volume":"10","author":"Cao","year":"2014","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1084\/jem.20041896","article-title":"VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis","volume":"201","author":"Hirakawa","year":"2005","journal-title":"Exp. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/1758-3284-3-40","article-title":"An overview of the rare parotid gland cancer","volume":"14","author":"Ho","year":"2011","journal-title":"Head Neck Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1002\/lio2.809","article-title":"Management and outcome of parotid mucoepidermoid carcinoma by histological grade: A 21-year review","volume":"7","author":"Taniuchi","year":"2022","journal-title":"Laryngoscope Investig. Otolaryngol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1016\/j.ejso.2018.11.008","article-title":"The number and ratio of positive lymph nodes are independent prognostic factors for patients with major salivary gland cancer: Results from the surveillance, epidemiology, and End Results dataset","volume":"45","author":"Qian","year":"2019","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1023\/A:1026404227624","article-title":"Transforming growth factor beta1 acts as an inducer of matrix metalloproteinase expression and activity in human bone-metastasizing cancer cells","volume":"17","author":"Duivenvoorden","year":"1999","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"G479","DOI":"10.1152\/ajpgi.00186.2012","article-title":"Chymase-mediated intestinal epithelial permeability is regulated by a protease-activating receptor\/matrix metalloproteinase-2-dependent mechanism","volume":"304","author":"Groschwitz","year":"2013","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1161\/01.RES.0000070112.80711.3D","article-title":"Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases: Structure, Function, and Biochemistry","volume":"92","author":"Visse","year":"2003","journal-title":"Circ. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.cccn.2004.04.019","article-title":"Human chymase degrades human fibronectin","volume":"347","author":"Okumura","year":"2004","journal-title":"Clin. Chim. Acta"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1007\/s12016-019-08769-2","article-title":"Mast Cell Biology at Molecular Level: A Comprehensive Review","volume":"58","author":"Komi","year":"2020","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"9017","DOI":"10.1073\/pnas.94.17.9017","article-title":"Chymase cleavage of stem cell factor yields a bioactive, soluble product","volume":"94","author":"Longley","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2144669","DOI":"10.1080\/2162402X.2022.2144669","article-title":"Chemokine switch regulated by TGF-\u03b21 in cancer-associated fibroblast subsets determines the efficacy of chemo-immunotherapy","volume":"11","author":"Vienot","year":"2022","journal-title":"Oncoimmunology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1038\/ncb1658","article-title":"Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells","volume":"9","author":"Gaggioli","year":"2007","journal-title":"Nat. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8678","DOI":"10.1038\/s41598-017-09062-y","article-title":"Silencing of TGF-beta1 in tumor cells impacts MMP-9 in tumor microenvironment","volume":"7","author":"Isayeva","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1038\/ni730","article-title":"Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells","volume":"2","author":"Tzachanis","year":"2001","journal-title":"Nat. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"307","DOI":"10.2174\/1568009054629663","article-title":"Antiproliferative efficacy of angiotensin II receptor blockers in prostate cancer","volume":"5","author":"Uemura","year":"2005","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1159\/000330169","article-title":"Anti-angiotensin and hypoglycemic treatments suppress liver metastasis of colon cancer cells","volume":"78","author":"Luo","year":"2011","journal-title":"Pathobiology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1681\/ASN.2003121009","article-title":"Effect of chymase inhibition on the arteriovenous fistula stenosis in dogs","volume":"16","author":"Jin","year":"2005","journal-title":"J. Am. Soc. Nephrol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/8267\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:29:31Z","timestamp":1760124571000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/8267"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,5]]},"references-count":42,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ijms24098267"],"URL":"https:\/\/doi.org\/10.3390\/ijms24098267","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,5]]}}}