{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T08:05:23Z","timestamp":1791446723658,"version":"4.3.3"},"reference-count":59,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,10,27]],"date-time":"2024-10-27T00:00:00Z","timestamp":1729987200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,10,27]],"date-time":"2024-10-27T00:00:00Z","timestamp":1729987200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP17K11509"],"award-info":[{"award-number":["JP17K11509"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Angiogenesis plays an important role in cancer growth and metastasis, and it is considered a therapeutic target to control tumour growth following anti\u2010angiogenic therapy. However, it is still unclear when tissues initiate angiogenesis during malignant transformation from premalignant condition and whether this premalignant condition could be a therapeutic target of anti\u2010angiogenic therapy. In this study, we aimed to analyse the onset of angiogenesis by evaluating morphological and functional alterations of microvessels during oral multistep carcinogenesis using a 4\u2010nitroquinoline 1\u2010oxide (4NQO)\u2010induced oral carcinogenesis mouse model. In the study, we initially confirmed that with the use of 4NQO, oral lesions develop in a stepwise manner from normal mucosa through oral epithelial dysplasia (OED) to oral squamous cell carcinoma (OSCC). Evaluation of CD31\u2010immunostained specimens revealed that microvessel density (MVD) increases in a stepwise manner from OEDs. Histological and functional analyses revealed the structural abnormalities and leakage of blood vessels had already taken place in OED. Then we evaluated the expression profiles of\n                    <jats:italic>Hif1a<\/jats:italic>\n                    and\n                    <jats:italic>Vegfa<\/jats:italic>\n                    along with hypoxic status and found that OED exhibited increased\n                    <jats:italic>Vegfa<\/jats:italic>\n                    expression under hypoxic conditions. Finally, we tested the possibility of OEDs as a target of anti\u2010angiogenic therapy and found that anti\u2010VEGFR2 neutralising antibody in OED slowed the disease progression from OED to OSCC. These data indicate that an angiogenic switch occurs at the premalignant stage and morphological, and functional alterations of microvessels already exist in OED. These findings also elucidate the tumour microenvironment, which gradually develops along with carcinogenic processes, and highlight usefulness of the 4NQO\u2010induced carcinogenesis model in the study of epithelial and stromal components, which will support epithelial carcinogenesis. \u00a9 2024 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6357","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T00:41:04Z","timestamp":1730076064000},"page":"423-433","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Anti\u2010VEGFR2 neutralising antibody slows the progression of multistep oral carcinogenesis"],"prefix":"10.1002","volume":"264","author":[{"given":"Yoichiro","family":"Shirogane","sequence":"first","affiliation":[{"name":"Department of Oral and Maxillofacial Pathology Osaka University Graduate School of Dentistry  Osaka Japan"},{"name":"Department of Removable Prosthodontics and Gerodontology Osaka University Graduate School of Dentistry  Osaka Japan"},{"name":"Department of Dentistry and Oral Surgery, Unit of Sensory and Locomotor Medicine, Division of Medicine, Faculty of Medical Sciences University of Fukui  Fukui Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4816-2132","authenticated-orcid":false,"given":"Yu","family":"Usami","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Pathology Osaka University Graduate School of Dentistry  Osaka Japan"},{"name":"Center for Infectious Disease Education and Research (CiDER) Osaka University  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Okumura","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Pathology Osaka University Graduate School of Dentistry  Osaka Japan"},{"name":"Osaka University Graduate School of Dentistry  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4148-1106","authenticated-orcid":false,"given":"Katsutoshi","family":"Hirose","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Pathology Osaka University Graduate School of Dentistry  Osaka Japan"},{"name":"Center for Infectious Disease Education and Research (CiDER) Osaka University  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Naniwa","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Pathology Osaka University Graduate School of Dentistry  Osaka Japan"},{"name":"Department of Oral Medicine Tokushima University Graduate School of Biomedical Sciences  Tokushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazunori","family":"Ikebe","sequence":"additional","affiliation":[{"name":"Department of Removable Prosthodontics and Gerodontology Osaka University Graduate School of Dentistry  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Toyosawa","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Pathology Osaka University Graduate School of Dentistry  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,10,27]]},"reference":[{"key":"e_1_2_8_2_1","volume-title":"WHO Classification of Tumours Editorial Board. Head and Neck Tumours","author":"Edward WO","year":"2023"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-00224-3"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics11071287"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0714.2011.01054.x"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11912-010-0150-z"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80108-7"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006536"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1093"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2009.04.007"},{"key":"e_1_2_8_12_1","first-page":"145","article-title":"A quantitative investigation of immunocytochemically stained blood vessels in normal, benign, premalignant and malignant human oral cheek epithelium","volume":"427","author":"Jin Y","year":"1995","journal-title":"Virchows Arch"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/1096-9896(2000)9999:9999<::AID-PATH652>3.0.CO;2-Y"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0714.2001.030008449.x"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0714.2003.00128.x"},{"key":"e_1_2_8_16_1","first-page":"775","article-title":"Vascular endothelial growth factor is a marker of tumor invasion and metastasis in squamous cell carcinomas of the head and neck","volume":"5","author":"Sauter ER","year":"1999","journal-title":"Clin Cancer Res"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.4248\/IJOS11077"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2011.10.003"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.top069906"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.00212"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2004.07.005"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2005.10.013"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-0999-3"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001044"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep20208"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2018.12.001"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0b013e31815bdbf5"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-18-0358"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1158\/1940-6207.CAPR-08-0211"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2005.12.014"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-8049(02)00094-1"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0088067"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature15250"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2009.12.092"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-3534"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/7628037"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.10681"},{"key":"e_1_2_8_38_1","first-page":"41","article-title":"Magnification endoscopy in esophageal squamous cell carcinoma: a review of the intrapapillary capillary loop classification","volume":"28","author":"Inoue H","year":"2015","journal-title":"Ann Gastroenterol"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1364\/BOE.9.001461"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2011.07.001"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1955.55"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-33037-2"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12079-016-0352-8"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-4521"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2023.1199225"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)65006-7"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000182903.16652.d7"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijom.2010.01.007"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2183"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/0026-2862(77)90141-8"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.5.3637"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-003-0784-3"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2017.1388484"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-019-1185-0"},{"key":"e_1_2_8_55_1","article-title":"Chemoprevention of 4NQO\u2010induced mouse tongue carcinogenesis by AKT inhibitor through the MMP\u20109\/RhoC signaling pathway and autophagy","volume":"2022","author":"Yin P","year":"2022","journal-title":"Anal Cell Pathol (Amst)"},{"key":"e_1_2_8_56_1","first-page":"659","article-title":"Vascular permeability factor\/vascular endothelial growth factor and its receptors in oral and laryngeal squamous cell carcinoma and dysplasia","volume":"77","author":"Denhart BC","year":"1997","journal-title":"Lab Invest"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oooo.2013.09.017"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/hed.2880160506"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2007.03.008"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00112.2013"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.6357","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/path.6357","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.6357","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T23:05:45Z","timestamp":1773011145000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.6357"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,27]]},"references-count":59,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,12]]}},"alternative-id":["10.1002\/path.6357"],"URL":"https:\/\/doi.org\/10.1002\/path.6357","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,27]]},"assertion":[{"value":"2024-04-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}